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Keywords:

  • clinical outcomes;
  • epidemiology;
  • venous thromboembolic disease

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Material and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Summary.  Clinical outcomes of patients diagnosed with venous thromboembolic disease (VTED) have rarely been assessed on large series of patients from single institutions. This was work based on our practice to routinely screen all suspected pulmonary embolism (PE) and deep venous thrombosis (DVT) patients with bilateral proximal and distal venous US was designed to evaluate survival, recurrence and cancer occurrence in patients diagnosed with symptomatic or asymptomatic DVT and to assess their relationship with the site of the DVT (proximal vs. distal, bilateral vs. unilateral). Our study is based on the cross-matching of the VTED register of the Grenoble University Hospital with the local Cancer Register and community mortality data. Survival analyses were performed with the Kaplan–Meier method; prognostic variables were tested using the log–rank test. A total of 1913 patients with a DVT of the lower limbs from 1993 to 1998 were included (57% women; mean age, 69 years). Of these, 1018 patients were diagnosed with proximal DVT (156 bilateral) and 895 distal DVT (112 bilateral). PE was associated in 760 patients. Patients with PE and no detected DVT were not included. At 2 years, adjusted survival rates were 80% in patients with unilateral-distal DVT, 67% in bilateral-distal, 72% in unilateral-proximal and 65% in bilateral-proximal DVT patients. The cumulated VTED recurrence rates were 7.7% in unilateral-distal DVT, 13.3% when DVT was bilateral-distal, 14% when unilateral-proximal and 13.2% when bilateral-proximal. The rate of new cancer was 6.4% in unilateral-distal DVT, 10.8% when it was bilateral-distal, 6.5% when unilateral-proximal and 6.1% when bilateral-proximal.

Based on a large series of unselected patients, our results show that the site of the DVT and principally the bilaterality provides important prognostic information that may be used in the setting up of medical strategies.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Material and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Deep venous thrombosis (DVT) of the lower limbs is a frequent disease associated with potentially life-threatening conditions such as pulmonary embolism (PE), but few epidemiological data regarding the incidence and natural history of DVT are available [1,2]. In patients presenting with acute symptomatic PE, the incidence of proximal (popliteal-femoro-iliac) and distal DVT are approximately 50% and 20%, respectively [3–5]. The natural history of distal DVT is poorly documented [6] and there is no consensus on the necessity of screening and treating patients presenting with isolated distal DVT [7,8]. There have been no methodologically satisfying clinical trials comparing anticoagulant treatment and no treatment for distal DVT; consequently, the latest American College of Chest Physicians (ACCP) recommendations propose treatment for symptomatic DVT with serial testing as an alternative [9]. Doppler ultrasound performance for detecting distal DVT is considered to be much less accurate than for detecting proximal DVT (sensitivity between 73% and 93% for detecting symptomatic distal DVT) [8] and worse for asymptomatic distal DVT [10]. However, recent publications report diagnostic performance nearly identical to phlebography when done by experienced teams [11,12].

Opinions differ on the matter of systematic ultrasound screening for bilateral DVT in patients with DVT suspected in a single limb: for many ultrasonographers, proximal testing of the symptomatic leg is sufficient [13,14], whereas others consider that both limbs should be systematically explored [15] and a third group suggests bilateral screening only in non-ambulatory patients [16]. However, a recent review in ‘Circulation’ stated that a complete color flow venous duplex examination has become the standard of care for assessment of DVT [17]. This study was designed to evaluate the clinical outcome of patients diagnosed with DVT (recurrence, cancer occurrence and survival) and to assess the relationship of these outcome variables with the site of the DVT (proximal vs. distal, bilateral vs. unilateral), using the records of the VTED Register of the Grenoble University Hospital [18] and the Isere Cancer Register [19].

Material and methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Material and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Study population

The Grenoble University Hospital has both a role as a tertiary referral center for the French Alps region and as a local hospital for the Grenoble area with internal medicine, surgery and obstetrics departments. Patients were referred to the vascular medicine unit for clinical suspicion of DVT or PE and for systematic evaluation in particular cases, such as high risk for venous thromboembolic disease (VTED) associated with disorders contraindicating anticoagulant prophylaxis (e.g. neurosurgery). From January 1993 to June 1998, all in- and outpatients diagnosed with an episode of DVT were considered for inclusion in the study.

Data collection

The data from all patients with DVT or PE diagnosed in our institution were prospectively recorded in a computerized register. The standardized data form contained the following information: date of diagnosis, name, sex, birth date and place, patient's address, clinical setting at the time of diagnosis (home, hospital), risk factors, symptoms and clinical signs of VTED, type and results of the diagnostic tests [duplex ultrasonography (duplex US), helical computed tomography (HCT) and ventilation–perfusion (V/Q) lung scan]. Duplex US was performed in every patient with suspected PE or DVT. This register, previously described [18], guaranteed exhaustive collection of DVT cases at the Grenoble University Hospital, no matter which clinical department patients originated from.

Inclusion criteria

In- and outpatients with at least one episode of documented acute DVT of the lower limbs (DVT with or without PE) diagnosed between January 1993 and June 1998 at the Grenoble University Hospital and living in the Isere department of France were included in the study. For patients presenting several episodes of DVT during the study period, only the first one was considered.

Patients with only superficial vein thrombosis or DVT in other locations (cerebral, portal system, ovarian and upper limbs) were not included. Patients with PE alone were also excluded because the structure of the register could not ascertain exhaustivity of such patients.

Diagnostic criteria

Diagnosis of DVT was always made by duplex US examination using ACUSON 128 XP and 210 DX, INTERSPECT ATL or ALOKA 500 machines with 3.5- and 7.5-MHz transducers. Complete venous US was performed by different operators trained in our hospital, all of them working as specialists in vascular medicine. The patient was examined in supine position for examination of the inferior vena cava, the iliac veins and the femoral veins (common, profundus and superficial), and in the sitting position for examination of the calf veins. Study of the calf veins included the posterior tibial and fibular veins, the gastrocnemius veins and the soleal veins on different incidences. The venous network was screened using two-dimensional real-time images, duplex modality and in some cases color flow ultrasound. The diagnosis of DVT was based on the observation of the absence of complete venous compressibility and absence of blood flow. Data on the quality of our method and reproducibility have been described previously [20]. The diagnosis of PE was concluded when there was proximal DVT associated with clinical thoracic signs of PE, an algorithm recently validated in both inpatients and outpatients by Perrier [21]. In the absence of proximal DVT on US, diagnosis of PE was based on dissociated perfusion deficiencies on V/Q lung scans (high-probability scans) according to the PIOPED criteria [22]. For patients with intermediate probability at V/Q lung scans, a helical computed tomography (CT) scan was performed as described previously [23]. In rare cases, pulmonary angiography was performed (high clinical probability with negative US and helical CT scan). Idiopathic thrombosis was defined as a DVT occurring in absence of neoplasm, known biological thrombophilia, personal history of VTED, a surgical procedure within the preceding months, pregnancy/postpartum or use of oral contraceptives.

Therapeutic regimen

Advice on the duration of anticoagulation was given at the time DVT was diagnosed, and then left to the discretion of the clinician in charge of patients. This advice was based on recommendations that had been previously decided by local consensus for treatment duration, inspired by the third and fourth recommendations of the ACCP [24,25]. Local consensus was at that time:

  • PE: 6 months when a triggering factor was clearly identified, 1 year or more if permanent thrombophilia (neoplasm, inherited thrombophilia).
  • Proximal DVT: 3 months with a triggering factor, 1 year or more if permanent thrombophilia.
  • Distal DVT (collecting vein): 6 weeks with a triggering factor, 3 months if permanent thrombophilia.
  • Muscular DVT: 10 days with a triggering factor, 6 weeks if permanent thrombophilia.

In addition, ambulation and compression therapy were considered in every patient.

Follow-up and collection of later events

The events recorded for the follow-up evaluation were the recurrence of a new VTED event, occurrence of cancer in the following 2 years and death.

  • Documentation of patient death was obtained from the computerized patient medical files from the Grenoble University Hospital and the demographic registers from the birth places of each patient for patients who died outside the hospital.
  • Occurrence of cancer was documented through the Isere Cancer Register, which systematically records every case of cancer diagnosed in the Isere department from the results of histological samples provided by pathology laboratories, and thus ensures the exhaustivity of cancer diagnosis data throughout the department. We queried the register for the 1994–1998 period by crossing our patient file with the register on the basis of the patient's last name, maiden name, first name and date of birth. In cases of different spellings, we used the town of residence, guaranteeing that the cancer diagnosis information was exhaustive [19].
  • Recurrence of VTED was also collected, but only from the hospital VTED register (some events diagnosed elsewhere might have been overlooked). Recurrence was defined as a new DVT location (new non-compressible area not contiguous with the initial one), proximal extension of the thrombus beyond a venous confluence, or a new embolic event (clinical suspicion of PE and documentation either by pulmonary V/Q lung scan or HCT). Recurrences were considered only when occurring at least 72 h after the initial diagnosis of DVT.

Statistical analyses

Statview© software (Abacus concept, Berkeley, CA, USA) was used for all statistical analyses. Descriptive statistics included median and corresponding ranges for continuous variables and percentages for qualitative variables. The Kaplan–Meier method was used to assess the risk for clinical events and to establish survival curves. Data were discontinued at the date of death, the date of the last contact or on 15 December 1998. Univariate analysis was carried out using the log–rank test. Finally, all of the variables found to be statistically significant in the univariate analysis, as well as age and sex, were introduced in a backward stepwise hierarchical Cox model. The results of these analyses were expressed as odds ratios (OR) and 95% confidence intervals (CI). We chose to show the results limiting analysis to 24 months in order to have at least 30 patients exposed to risk.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Material and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Patient characteristics

Between 20 January 1993 and 24 June 1998, 2711 consecutive patients with VTED were recorded in the VTED Registry of the Grenoble University Hospital. Among them, 798 were excluded because they were living outside of the Isere department (492) or because they had only superficial vein thrombosis (146) or PE with no DVT (160). The remaining 1913 patients were included in the study. Their median follow-up was 1.5 years, and their main characteristics are shown in Table 1.

Table 1.  Characteristics of the 1913 study patients
Number of patients1913
Average age [extremes], median69 years [0–100], 73
Sex57% women
Median follow-up18 months [0–65]
Hospitalized73.5%
Symptomatic thrombosis in lower limb71%
Thoracic symptoms (dyspnea, hemoptysis)19%
Past history of VTE25%
Genetic thrombophilia2%
Venous insufficiency20%
Surgery  <1 month33%
Known cancer22%
Idiopathic thrombosis23%

Characteristics of the DVT event

DVT characteristics are shown in Table 2. Compared with distal unilateral DVT, bilateral distal DVT was characterized by a higher frequency of known cancer (26% vs. 17%, P = 0.002), decompensate cardiac or pulmonary pathology (11.6% vs. 6.1%, P = 0.04), venous insufficiency (29% vs. 20%, P = 0.03) and higher age (60% of patients over 70 years vs. 40%, P = 0.03). Being recently bedridden (less than 10 days) was very close to being significant (40% vs. 31%, P = 0.06). There was no significant difference for the other risk factors or for patients’ ambulatory status.

Table 2.  Topographic characteristics of thromboembolic events among the 1913 patients
  Associated PE
Number of patients1913760 (39%)
Unilateral distal783 (41%)230 (29%)
Bilateral distal112 (6%)50 (45%)
Unilateral proximal862 (45%)397 (46%)
Bilateral proximal156 (8%)83 (53%)

Outcomes/multivariate analysis

Five-hundred and fifty-one patients (28.8%) died during follow-up, 174 (9.1%) experienced recurrence of VTED and 91 patients (4.71%) presented a new cancer in the 2-year following diagnosis. The survival rate for the entire population was 80% [78%–82%] at 1 year and 74% [71.8%–76.2%] at 2 years. The cumulated rate of newly diagnosed cancer was 4.7% at 1 year [3.5%–5.9%] and 6.6% [5.2%–8.0%] at 2 years. The cumulated recurrence rate was 5% [4.5%–5.5%] at 1 year and 8% [7.2%–8.8%] at 2 years.

Rates of survival, occurrence of new cancer and recurrence of VTED differ according to the topography of DVT in univariate analysis, as shown in Figs. 1–3.

image

Figure 1. Kaplan–Meier estimates of survival in patients with a thromboembolic event depending on the topography of the DVT.

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image

Figure 2. Kaplan–Meier estimates of cumulative incidence of newly diagnosed cancer within 2 years depending on the topography of the DVT.

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image

Figure 3. Kaplan–Meier estimates of cumulative incidence of a recurrent venous thromboembolism during follow-up depending on the topography of the DVT.

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The complete results of the multivariate analysis with OR and CI are shown in Tables 3–5.

Table 3.  Multivariate regression model of clinical risk factors for mortality during follow-up. Sex and PE are non-significant
 No. of patientsOR [CI]P-value
Topography:
 Distal unilateral7831 0.01
 Distal bilateral1121.48 [1.06–2.09] 0.02
 Proximal unilateral8621.21 [1–1.47] 0.02
 Proximal bilateral1561.52 [1.14–2] 0.004
Cardiopulmonary morbidity1201.96 [1.48–2.55]<0.0001
Known cancer4282.97 [2.49–3.5]<0.0001
Age category
 <60 years4920.28 [0.21–0.37]<0.0001
 60–75 5800.6 [0.5–0.72]<0.0001
 >75 years8411<0.0001
Table 4.  Multivariate regression model of clinical risk factors for recurrence of DVT during follow-up. Age, sex, idiopathic thrombosis and PE are non-significant
 No. of patientsOR [CI]P
Topography:
 Distal unilateral78310.004
 Distal bilateral1122 [1.1–3.7]0.03
 Proximal unilateral8621.8 [1.3–2.6]0.0005
 Proximal bilateral1561.5 [0.8–2.8]0.15
History of thromboembolic disease4741.7 [1.3–2.4]0.0004
Known cancer4282.1 [1.5–3]<0.0001
Table 5.  Multivariate regression model of clinical risk factors for the occurrence of newly diagnosed cancer within 2 years. Age and PE are non-significant
 No. of patientsOR [CI]P
Topography:
 Distal unilateral78310.007
 Distal bilateral1122.5 [1.3–4.8]0.005
 Proximal unilateral8620.8 [0.5–1.3]0.3
 Proximal bilateral1561.2 [0.2–1.1]0.6
Idiopathic thrombosis4391.6 [1–2.4]0.05
Female sex10950.6 [0.4–0.9]0.03

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Material and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

We investigated the association of the topography of DVT diagnosed following routine bilateral proximal and distal US with the incidence of clinically significant events from a prospective large cohort of 1913 patients with VTED. Nearly 75% of the patients were inpatients at the time of diagnosis and were representative of a population hospitalized without exclusion (pregnant women, intensive care patients, etc.). Their main characteristics included a high average age (69 years) and a high proportion of neoplasm known at the time of diagnosis of DVT (20%).

The proportion of distal DVT that we diagnosed (47%) was slightly higher than figures found in the literature, where distal DVT makes up 15% [8,26] to 33 % [27–29] of the diagnosed cases of DVT. This may due to our routine practice of systematic screening of calf veins of both limbs. There was almost as much distal DVT (47%) as proximal DVT (53%) in our sample. Bilateral distal DVT was associated with a rate of PE as high as unilateral proximal DVT and significantly higher than unilateral distal DVT (P < 0.001).

On mortality, recurrence and incidence of a new neoplasm in the 2-year period following examination, we noted that topography was significant in univariate analysis. Patients with bilateral distal DVT have similar outcomes as the patients with proximal DVT:

  • Two-year survival rate of 72% [70.3%–73.7%] for patients with unilateral proximal DVT, 65% [61%–69%] for patients with bilateral proximal DVT and 67% [62%–72%] for patients with bilateral distal DVT.
  • Two-year recurrence of VTED: 14% [12.5%–15.5%] for patients with unilateral proximal DVT, 13.2% [9.6%–16.8%] for patients with bilateral proximal DVT and 13.3% [10.3%–16.3%] for patients with bilateral distal DVT.
  • Two-year occurrence of new cancer: 6.5% [4.1%–8.9%] for patients with unilateral proximal DVT, 6.1% [1.5%–10.7%] for patients with bilateral proximal DVT, and 10.8% [4.6%–17%] for patients with bilateral distal DVT.

The results comparing unilateral and bilateral distal DVT showes a significant difference in prognosis for all three evaluated items. Patients with unilateral distal DVT experience better outcomes: 80% [79%–81%] survival, 6.4% [4.2%–8.6%] new cancer and 7.7% [6.7%–8.7%] recurrence at 2 years. Our results confirm in an unbiased large sample of patients with deep vein thrombosis of the lower limbs that unilateral calf DVT is less severe than proximal DVTs when comparing rates of recurrences, cancer occurrence and mortality. This is well described in the medical literature [5,30,31] and has led to a difference in managing these two subsets of the disease as far as anticoagulation and its duration are concerned.

On the other hand, multivariate analysis showed no influence of absence or presence of PE on survival prognosis, occurrence of new cancer and recurrence in patients diagnosed with symptomatic or asymptomatic DVT. In the analysis of a randomized-controlled database, Douketis found that patients with PE were as likely as those with DVT to develop recurrent VTE [32]. Our findings suggest among patients with DVT with or without PE that the topography of the DVT may be clinically more significant than the presence of PE in patient's prognosis.

The limits of our study include the absence of precise information on the duration of anticoagulant treatment that patients were taking and the possibility that certain patients had a recurrence when not in the hospital. We therefore may have missed recurrences diagnosed outside the hospital by private practitioners but only if patients were not later rehospitalized; consequently, the incidence of recurrence is probably slightly underestimated. However, we do not believe that this biased the calculation of risk factors associated with recurrence.

Bilateral distal DVT is associated with an outcome similar to the outcome of proximal DVT. This small subgroup of patients (112) had as poor a prognosis as patients with bilateral proximal DVT in terms of mortality, the incidence of recurrence and the occurrence of neoplasm. The literature includes very few studies on bilateral thromboses, which are more frequently associated with neoplasm in Rance's retrospective study [33], in a prospective study by Prandoni [34] and more recently in a prospective study by Bura et al. [35]. In our study, bilateral distal thromboses are a significant independent prognostic factor in multivariate analysis. These bilateral distal thromboses probably reflect a more intense thrombophilic status suggested by the analysis of risk factors, it is particularly associated with: cancer, age, congestive heart failure or respiratory failure, venous insufficiency and being bedridden.

This study is to our knowledge the first large study based on unselected patients, inpatients as well as outpatients, showing that the prognosis of patients with distal bilateral DVT diagnosed by routine bilateral proximal and distal venous US is comparable with the prognosis of patients with proximal DVT. This is an observational study, and it is not possible to draw practical knowledge from these data on a potentially different therapeutic management. However, this study has shown the prognostic value of diagnosing bilateral distal DVT by routine bilateral lower limb US in patients who were either symptomatic of DVT (both ambulatory or hospitalized) or at risk of having DVT due to hospitalization or a diagnosis of PE. Based on this prognostic information, we believe that in these patients systematic evaluation of the venous system as routinely undertaken by our department is warranted.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Material and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

We thank Linda Northup for help in editing the paper.

This work was supported by a grant from the Délégation Régionale de la Recherche Clinique de Grenoble.

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  1. Top of page
  2. Abstract
  3. Introduction
  4. Material and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
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