Outcomes for Inpatients with Normal Findings on Whole-leg Ultrasonography: A Prospective Study

Article Outline

• Abstract
• Materials and Methods
  • Study Design
  • Patients
  • Data Collection
  • Whole-leg Ultrasonography
  • Follow-up
  • Analysis
• Results
• Discussion
  • Limitations
• Conclusions
• Acknowledgments
• References
• Copyright

Abstract 

Background

Ultrasonography is used routinely for ruling out suspected deep vein thrombosis in hospitalized patients, although most evidence supporting this strategy is derived from the outpatient setting. This study aimed to estimate the rate of venous thromboembolism when anticoagulant therapy was withheld from inpatients with normal findings on whole-leg ultrasonography.

Methods

As part of a prospective multicenter cohort study, 1926 medical and surgical inpatients with clinically suspected deep vein thrombosis during their stay were enrolled. Ultrasonography of all lower extremities was performed by board-certified vascular medicine physicians using a standardized examination protocol. Deep vein thrombosis was detected in 395 patients (20%). Anticoagulant therapy was withheld from patients with normal findings, and 523 of them were randomly selected for follow-up. The main outcome measure was 3-month incidence of symptomatic venous thromboembolism.

Results

A total of 513 patients with normal findings on ultrasonography successfully completed 3 months of follow-up, 9 patients were lost to follow-up, and 1 patient received anticoagulant therapy during follow-up. Three patients (0.6%) experienced nonfatal symptomatic venous thromboembolic events confirmed by objective testing. The cause of death was judged to be possibly related to pulmonary embolism for 7 other patients (1.3%). Overall, the 3-month rate of venous thromboembolism was 1.9% (10/513; 95% confidence interval, 0.9-3.5).

Conclusion

Although withholding anticoagulant therapy after a single negative whole-leg ultrasonography seems to be safe, up to 3.5% of inpatients may nevertheless develop venous thromboembolism in the next 3 months. Further study is warranted to determine whether this strategy is equivalent to serial compression ultrasonography limited to proximal veins.

Keywords: Cohort studies, Inpatients, Veins/ultrasonography, Venous thrombosis

Deep vein thrombosis of the lower extremity is a common complication among patients hospitalized for acute medical illness or surgery.¹, ², ³ Accurate diagnosis and appropriate treatment of this disease are essential because of the risk for potentially fatal pulmonary embolism in untreated patients, whereas anticoagulant therapy exposes patients without deep vein thrombosis to an unnecessary risk of hemorrhage.⁴, ⁵

Ultrasonography of the lower extremity is routinely used for guiding the anticoagulant therapy decision in hospitalized patients with suspected deep vein thrombosis.⁶, ⁷ Several prospective studies have shown the safety of whole-leg ultrasonography for ruling out deep vein thrombosis in symptomatic outpatients without further testing.⁸, ⁹, ¹⁰, ¹¹, ¹² Although requiring additional skills and experience, whole-leg ultrasonography is a convenient alternative to compression ultrasonography limited to proximal veins, which needs to be repeated 1 week after an initial normal test result in all or selected higher-risk patients.¹³ However, the diagnostic performance of whole-leg ultrasonography in outpatients might not necessarily apply to inpatients because of different referral patterns and higher prevalence of risk factors.

By using the original data from a multicenter prospective cohort study, we estimated the 3-month incidence of symptomatic venous thromboembolic events after withholding anticoagulant therapy from inpatients with normal findings on a single whole-leg ultrasonography performed for suspected deep vein thrombosis.

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Materials and Methods 

Study Design 

As part of a prospective cohort study, the present analysis focused on inpatients with clinically suspected deep vein thrombosis during their stay in 55 hospitals (including 17 university-affiliated hospitals, 22 general hospitals, and 16 private hospitals) evenly distributed throughout metropolitan France. Depending on the site, the enrollment period consisted of 1 to several predefined days distributed between November 2004 and January 2006. This strategy was planned to avoid overrepresentation of patients enrolled in larger hospitals and to limit the potential for seasonal bias.¹⁴ In the original study, we followed up all patients with objectively confirmed venous thromboembolism (ie, pulmonary embolism, deep vein thrombosis, and superficial thrombophlebitis) and a subset of patients with unconfirmed venous thromboembolism. We generated lists of patients with unconfirmed venous thromboembolism and stratified them according to hospital and enrollment period. A random starting point within each stratified list was used to generate random numbers to select for follow-up a number of patients with unconfirmed venous thromboembolism equal to the number of patients with confirmed venous thromboembolism from each stratum. This study was approved by the Ethics Committee of the French Data Agency.

Patients 

For the purposes of the present analysis, we selected all patients 18 years of age or older who were inpatients at the time ultrasonography was performed and who had been hospitalized for surgical or medical conditions other than suspected venous thromboembolism. We excluded patients with concurrent signs or symptoms suggestive of pulmonary embolism because symptomatic pulmonary embolism was a study outcome. Patients receiving anticoagulant therapy at baseline or during the 3-month follow-up period for reasons other than venous thromboembolism were excluded from the analysis to prevent confounding results.

Data Collection 

For each patient, baseline characteristics were prospectively collected by vascular medicine physicians using an electronic case-report form. Standardized definitions were used for the assessment of comorbid conditions and clinical examination findings at presentation. The vascular medicine physicians documented the 10 clinical features comprising the simplified clinical model for assessment of deep vein thrombosis published by Wells et al,¹⁵ but they were not asked to compute the pretest probability estimate for deep vein thrombosis. The pretest probability estimate was not used for patient diagnostic management in this study.

Whole-leg Ultrasonography 

All enrolled patients underwent bilateral ultrasonography of the lower extremities performed by vascular medicine physicians using a standardized examination protocol. All participating vascular medicine physicians were board-certified and had at least 2 years of experience with ultrasonography. High-resolution 5- to 7.5-MHz linear transducers were used. The proximal veins were examined from the common femoral vein in the groin area to the trifurcation of the popliteal vein by moving the transducer distally and applying gentle compression along the deep venous system with the patient in the supine position. The calf veins were evaluated to the ankle level using ultrasonography in a similar fashion to that of the proximal veins, with the patient in the sitting position with the legs hanging down. The great and small saphenous veins also were evaluated for superficial vein thrombosis.

The diagnostic criterion for a patient's first episode of deep vein thrombosis was the incompressibility of the vein in the transverse plane. For gastrocnemius and soleal vein thrombosis only, the diagnostic criterion was incompressibility of the vein combined with the absence of venous flow after distal compression.¹⁶ The diagnostic criterion for recurrent deep vein thrombosis was the incompressibility of a previously normal venous segment in patients with a history of deep vein thrombosis.

Patients with deep vein thrombosis were recommended anticoagulant therapy in accordance with current guidelines.¹⁷, ¹⁸ Anticoagulant therapy with intermediate doses of low-molecular-weight heparin for 4 weeks was suggested for patients with superficial vein thrombosis.¹⁷, ¹⁸ Anticoagulant therapy was withheld from patients with normal findings on ultrasonography. All patients were instructed to return to the hospital if they experienced symptoms or signs of venous thromboembolism after discharge.

Follow-up 

Follow-up of randomly selected patients with normal findings on baseline ultrasonography consisted of a structured chart review and telephone interviews with the patients, their relative, or their family physician 3 months after enrollment. Patients were asked for symptoms of venous thromboembolism, hospital readmission, visit, anticoagulant use, and general health. Medical records were reviewed for all hospital readmissions during the follow-up period. If follow-up data could not be obtained, the patient's living status was ascertained using his birthplace census record.

All deaths and clinically suspected venous thromboembolic events during follow-up were reviewed by a central adjudication panel using salient information obtained from the medical record, death certificate, and attending physician interview. Patients were judged to have pulmonary embolism if they had a high-probability ventilation-perfusion lung scan, a positive computed tomographic pulmonary angiography, or a positive pulmonary angiography. Suspicion of deep vein thrombosis was confirmed by whole-leg ultrasonography. The adjudication panel assigned the immediate and underlying causes of death and classified the death as certainly related to venous thromboembolism, possibly related to venous thromboembolism (if the cause of death could not be clearly established), or definitely not related to venous thromboembolism.

Analysis 

Descriptive statistics are presented as numbers and percentages for categoric variables or median and 25th and 75th percentiles for continuous variables. A sample size of 500 untreated inpatients with normal ultrasonography allowed a 95% confidence interval (CI) with an upper limit of 5%, assuming a 3-month incidence of venous thromboembolism point estimate lower than 3%. Exact 95% CIs were calculated from the binomial distribution using Stata 9 (Stata Corp, College Station, Tex).

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Results 

A total of 1926 inpatients with a clinical suspicion of deep vein thrombosis were enrolled and underwent whole-leg ultrasonography (Figure). Women comprised 59% of all patients, the median age was 68 years (interquartile range, 52-78 years), and 28% of the patients had a likely pretest probability of deep vein thrombosis using the Wells clinical prediction rule (Table 1).

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• Figure. 

  Patient enrollment flow-chart.

Table 1. Baseline Characteristics

Characteristics	Patients with Confirmed Deep Vein Thrombosis (n = 395)	Patients with No Evidence of Deep Vein Thrombosis
		Sampled for Follow-up (n = 523)	Not Sampled for Follow-up (n = 782)
Median age (interquartile range), y	70(55-80)	67(52-78)	67(50-78)
Women, n (%)	235(59.5)	320(61.2)	453(57.9)
Clinical conditions, n (%)
Active cancer	100(25.3)	81(15.5)	131(16.7)
Paralysis, paresis, or recent plaster immobilization of the lower extremities	32(8.1)	30(5.7)	44(5.6)
Recently bedridden for ≥3 d	110(27.8)	106(20.3)	195(24.9)
Major surgery within the previous 12 wk	114(28.9)	119(22.7)	199(25.4)
Previously documented deep vein thrombosis	61(15.4)	34(6.5)	48(6.1)
Median duration of symptoms (interquartile range), da	3(2-5)	3(2-8)	4(2-8)
Clinical signs at presentation, n (%)
Localized tenderness along the deep venous system	59(14.9)	41(7.8)	36(4.6)
Entire leg swelling	68(17.2)	62(11.8)	96(12.3)
Calf swelling ≥3 cm	184(46.6)	202(38.6)	303(38.7)
Pitting edema	83(21.0)	99(18.9)	160(20.4)
Collateral superficial veins (nonvaricose)	7(1.8)	4(0.8)	3(0.4)
Alternative diagnosis at least as likely as deep vein thrombosis, n (%)	49(12.4)	292(55.8)	433(55.4)
Likely pretest probability of deep vein thrombosis (score ≥2), n (%)b	207(52.4)	111(21.2)	160(20.5)

Deep vein thrombosis was detected by ultrasonography in 395 patients (20%). The deep vein thrombosis involved the proximal veins in 155 cases (8%) and was limited to the calf veins in 240 cases (12%) (Figure 1). Isolated gastrocnemius and soleal vein thromboses accounted for 107 of 240 cases of calf deep vein thrombosis. The deep vein thrombosis was unilateral in 312 patients (16%) and bilateral in 83 patients (4%). The prevalence of all and proximal deep vein thrombosis was 38% (207/538) and 20% (109/538) for patients with likely pretest probability and 13% (188/1388) and 3.3% (46/1388) for patients with unlikely pretest probability, respectively. Of the 1531 patients with no evidence of deep vein thrombosis, 95 (6%) were found to have an alternative cause of symptoms during ultrasonography, including superficial vein thrombosis (n=63), calf hematoma (n=12), popliteal cyst (n=9), extrinsic deep vein compression (n=4), arteriopathy (n=4), and partial muscle rupture (n=3).

The negative cohort consisted of 523 patients after exclusion of 63 patients with superficial vein thrombosis for whom treatment with intermediate doses of low-molecular-weight heparin was advocated in accordance with current guidelines, 163 patients receiving long-term anticoagulant treatment at baseline, and 782 patients who were not sampled for follow-up in accordance with the study protocol (Figure 1). Of these, 513 patients successfully completed 3 months of follow-up, 9 patients were lost to follow-up, and 1 patient was excluded because of the use of anticoagulant therapy for recurrent atrial fibrillation during follow-up. None of the 9 patients lost to follow-up died within 3 months of enrollment. A total of 327 patients (63%) used prophylaxis against venous thromboembolism during follow-up with a median duration of 15 days; 61 patients used mechanical prophylaxis, 131 patients used pharmacologic prophylaxis, and 135 patients used both modalities.

During the 3-month follow-up, 3 untreated patients (0.6%, 95% CI, 0.1-1.7) experienced nonfatal symptomatic venous thromboembolism confirmed by objective testing, including pulmonary embolism in 1 patient and deep vein thrombosis in 2 patients (Table 2). Forty-one patients (8%) died during follow-up (Table 3). The immediate cause of death was judged to be possibly related to pulmonary embolism in 7 patients (1.3%) (Table 2). Forty-eight additional patients were rehospitalized within 90 days of enrollment. None of these hospital readmissions were motivated by clinically suspected venous thromboembolism. Overall, the 3-month rate of fatal and nonfatal venous thromboembolism was 1.9% (10/513, 95% CI, 0.9-3.5).

Table 2. Characteristics of Patients with Fatal and Nonfatal Symptomatic Venous Thromboembolic Events during Follow-up^a

PE=pulmonary embolism; COPD=chronic obstructive pulmonary disease.

Table 3. Causes of Death During Follow-up (n=41)

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Discussion 

Ultrasonography is routinely used for guiding the anticoagulant therapy decision in inpatients with suspected deep vein thrombosis, although most evidence supporting this diagnostic strategy is derived from the outpatient setting. In this study, which is the largest outcome study conducted to date in inpatients, the rate of symptomatic venous thromboembolism was 1.9% (95% CI, 0.9-3.5) among untreated patients with normal findings on a single whole-leg ultrasonography.

The evaluation of deep vein thrombosis using whole-leg ultrasonography instead of repeated compression ultrasonography of proximal veins distinguishes our study from previous research.¹⁹, ²⁰ Although convenient in routine practice, whole-leg ultrasonography remains controversial because of a probably outdated perception that ultrasonography is inaccurate in detecting calf thrombi.²¹, ²² Actually, our estimate of 3-month venous thromboembolism in untreated inpatients was consistent with those observed in studies using repeated compression ultrasonography of proximal veins (1.8% [95% CI, 0.2-6.4]²⁰ and 10% [95% CI, 1.2-31]¹⁹). There also is growing evidence that whole-leg ultrasonography is equivalent to repeated compression ultrasonography of proximal veins for excluding deep vein thrombosis in the outpatient setting.⁸

Another issue with whole-leg ultrasonography is the consistently high reported prevalence of isolated distal deep vein thrombosis detected with this procedure.¹³, ²³ The prevalence of isolated distal deep vein thrombosis (12%) in our study was consistent with the rates reported by studies using contrast venography (8%²⁴ and 13%²¹). Consistent with previous reports,⁸, ²⁵ isolated gastrocnemius and soleal vein thromboses accounted for 44% (107/240) of distal deep vein thromboses in our study. Although current guidelines recommend anticoagulant therapy for patients with distal deep vein thrombosis,¹⁸ the management of isolated gastrocnemius or soleal vein thrombosis remains controversial. Published data suggest that the risk of gastrocnemius or soleal thrombi propagating to popliteal veins is as low as 3%,²⁶ emphasizing the potential for unnecessary anticoagulant therapy with whole-leg ultrasonography.¹³, ²³

Our estimate of 3-month venous thromboembolism in untreated inpatients was higher than that observed in outpatients or mixed populations (range, 0.2%-1.4%).⁸, ²³ There are several potential explanations for this finding. First, false-negative cases of ultrasonography might be more frequent in inpatients than outpatients. However, this was unlikely because comparable estimates of sensitivity and specificity have been reported for ultrasonography in inpatients²¹, ²², ²⁷ and outpatients.²⁸

Second, venous thromboembolism may develop secondarily during follow-up in patients with true-negative results on ultrasonography. This is more likely to occur among inpatients than outpatients because of more severe underlying diseases and higher prevalence of risk factors.²⁰ Moreover, hospital admission has been shown to be an independent risk factor for venous thromboembolism in epidemiologic studies.² This emphasizes the importance of appropriate prophylaxis against venous thromboembolism after normal findings on whole-leg ultrasonography for at-risk patients.²⁹

Third, the rate of venous thromboembolism might be overestimated in our study. Only 3 of the 10 events were objectively confirmed; the 7 others were deaths judged to be possibly related to pulmonary embolism by our central adjudication panel. The rate of nonfatal symptomatic venous thromboembolism in our study (0.6%) was comparable to that reported for outpatients.⁸, ⁹, ¹⁰, ¹¹, ¹² Consistent with previous studies of inpatients,²⁰ the overall mortality rate was higher in our study (8%) than that reported for outpatients (range, 0%-2.4%).⁸, ⁹, ¹⁰, ¹¹, ¹², ¹⁵, ³⁰

Limitations 

Our study has several potential limitations. First, not all patients with negative results who were enrolled in the study were prospectively followed up. However, this was unlikely to affect our estimates of venous thromboembolism because the patients with negative results who were followed up were randomly selected and therefore had baseline characteristics comparable to the patients with negative results who were not followed up.

Second, concerns may exist regarding the homogeneity of the diagnostic procedure in our study. All ultrasonography tests were performed by board-certified vascular medicine physicians using a standardized examination protocol. Previous studies have shown that complete compression ultrasonography yields satisfactory interrater agreement.³¹ Actually, it can be argued that the large number of vascular medicine physicians is a strength of our study and supports the generalizability of our findings.

Third, although patients with superficial vein thrombosis were followed up in the original study, they were excluded from the present analysis to prevent confounding by anticoagulant therapy. Indeed, treatment with intermediate doses of low-molecular-weight heparin for 4 weeks is advocated by current guidelines for these patients.¹⁷, ¹⁸ Patients with symptomatic superficial vein thrombosis accounted for 3.3% (63/1926) of all patients and may have contributed to underestimating venous thromboembolism during follow-up, although their exclusion from the analysis was consistent with a previous study.¹⁰

Fourth, whole-leg ultrasonography was used for the diagnostic management of suspected deep vein thrombosis during follow-up, with the potential for incorporation bias. As noted by others,¹¹ this was unlikely to occur given the high sensitivity of repeated compression ultrasonography for detecting deep vein thrombosis missed on initial evaluation.

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Conclusions 

Although withholding anticoagulant therapy from inpatients with normal findings on a single whole-leg ultrasonography seems to be safe, up to 3.5% of them might develop venous thromboembolism in the next 3 months. Randomized controlled trials are warranted to determine whether serial compression ultrasonography of proximal veins and whole-leg ultrasonography are equivalent strategies for ruling out suspected deep vein thrombosis in inpatients.

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Acknowledgments 

A list of the investigators who participated to the study is available at http://recherche-clinique.ujf-grenoble.fr/OPTIMEV/index.htm. The authors are indebted to Carole Rolland and Céline Genty for data management and to Catherine Blanie, Maryline Blanc, Marion Proust, Sandrine Massicot, Ludovic Delhomme, Catherine Maillard, and Caroline Bonnet for data monitoring and patient follow-up. Linda Northrup from English Solutions (Voiron, France) provided assistance in preparing and editing the article.

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