Single Comprehensive Ultrasound to Rule Out DVT in High-Risk Patients

Design: Prospective clinical cohort study.

Patients: 478 sequentially enrolled patients evaluated for suspected symptomatic deep vein
thrombosis of the leg, reporting to the LDS Peripheral Vascular Laboratory. Vascular
technicians will screen patients for study entry with a simple questionnaire. Those meeting
screening criteria will then be interviewed by the study coordinator to verify they meet
inclusion criteria, have no exclusions, and provide informed consent.

To be enrolled in this study a patient must:

1. Be referred for suspected first ipsilateral episode of acute DVT of the lower
extremities.

2. Be > 18 y.o.

3. Provide written informed consent.

Patients will be excluded if:

1. Pregnant.

2. Phlebotomy cannot be performed to obtain a sensitive d-dimer assay.

3. Compression ultrasonography cannot be performed due to physical or technical reasons.

4. Long-term follow-up will not be possible due to geographic inaccessibility,
homelessness or lack of a telephone.

5. Therapeutic doses of an anticoagulant have been received for more than 24 hours before
enrollment.

6. Informed consent cannot be obtained.

7. Long term anticoagulation will be required for another diagnosis (e.g. atrial
fibrillation).

Demographic and medical history information:

Study clinical variables are obtained from the enroller interview and electronic medical
record at entry and included in a computerized clinical database. They include age, sex,
weight, inclusion and exclusion criteria, and clinical information necessary to create the
pre-test clinical score. Demographic information and basic biometrics (gender, height,
weight, leg circumference) will be obtained and recorded by the study coordinator. Informed
consent documents will be obtained and stored according to the policies of the Institutional
Review Board. All female patients will undergo urine or serum pregnancy testing prior to
study entry.

Measurements: A research clinician will perform a brief clinical assessment specific for
determining pre-test probability of DVT prior to evaluation with diagnostic tests. This
formalized scoring system has been validated in a prior study. Patients with a clinical
score of “DVT unlikely” will undergo comprehensive duplex ultrasonography. If normal,
patients will be followed for clinical events as described below.

Patients in the cohort not analyzed (comprising a group with lower pre-test probability of
DVT) will go on to diagnostic testing and further care by the referring physician.
Demographic information will be used in the descriptive portions of the study to demonstrate
risk prevalence, but patients will not be followed for clinical outcome.

The scoring system to determine pre-test probability is that described by Wells et al.

Comprehensive, real-time B-mode ultrasonography with color Doppler analysis (CDU) will be
performed on patients with a pre-test probability of “DVT Likely.".

A standardized technique will be used for the CDU examination. Compressibility of the veins
will be assessed. The results will be categorized as normal if all imaged venous segments
are fully compressible, as abnormal if a noncompressible segment is identified, or as
inadequate for interpretation.

Interpretation will be performed by experienced vascular surgery staff according to
protocols currently in use at LDS Hospital. Findings will be redacted to specific data
fields by the interpreting surgeon according to a form generated for this purpose. The form
will be completed by the interpreting surgeon and added to the patient logbook for entry
into the database by the data entry clerk.

Interobserver variability will be limited by using a priori criteria for a positive and
negative study5 and by using only two interpreters, both with substantial experience and
expertise. Interobserver agreement for this technique has been found to be high.

If the result of initial CDU is normal (no DVT identified), anticoagulation will be
withheld, regardless of symptoms.

If the result of testing is abnormal (DVT identified), anticoagulation will be given unless
contraindicated, according to established protocols.

Subjects whose results are classified as inadequate for interpretation will have reasons
logged and be excluded from analysis. They will receive further management according to the
discretion of the emergency physician.

Long-Term Follow-up Patients in the two observation cohort (negative CDU) will be undergo
three months of clinical follow-up, a strategy used in many diagnostic trials for DVT.
Patients will be instructed to return immediately to our emergency department if they have
symptoms or signs of venous thrombosis or pulmonary embolism. A thromboembolic disease
specialist will assess them at 3 months by telephone interview.

At the follow-up assessment, an interval history will be taken with emphasis on specific
symptoms (including leg pain, tenderness and swelling, chest pain, dyspnea, hemoptysis, and
syncope), hospitalization, interval evaluation for DVT or PE and use of anticoagulants. For
all patients who die, the cause of death will be determined from autopsy or by independent
clinical review if autopsy cannot be obtained.

Results of the follow-up assessment will be entered on a data sheet by the assessing
clinician created for this purpose. This sheet will be added to the logbook by the study
coordinator and information appended to the database by the data entry clerk. The
evaluating clinician will refer patients for appropriate testing for thromboembolic disease
based on clinical suspicion. Patients suspected of having deep vein thrombosis will be
referred for compression ultrasonography. If CDU is abnormal, patients will be treated with
anticoagulation therapy. If normal, patients will be referred for venography (the current
gold standard test) to exclude the diagnosis of DVT. Patients suspected of having pulmonary
embolism will undergo objective testing with ventilation-perfusion lung scanning and, if
indicated, pulmonary angiography or high-resolution computed tomography. Qualified
physicians blinded to the subject’s cohort will perform interpretation of all testing.

Main Outcome Measures and Statistical Comparisons:

Primary outcome measure will be venous thrombosis, pulmonary embolism (VTE) and death from
thromboembolic disease during follow-up confirmed by objective testing in the 3 months
following enrollment.

The study will be designed to estimate the event rate of thromboembolic disease and death
attributable to thromboembolic disease in the normal cohort during the three-month follow-up
period. An exact 95% confidence interval that excludes a rate of VTE of 3% will be defined
as clinically acceptable, in accordance with previous trials of DVT diagnosis.

Adjudication of outcomes:

A panel of three independent physicians with established expertise in venous thromboembolism
will be named to adjudicate all suspected events of VTE and all diagnostic tests for VTE
occurring during the follow-up period. Simple majority will resolve disputes.

Methodological Issues and Avoidance of Bias Entering consecutive patients into the study
will avoid selection bias. To avoid bias during the initial testing period, we have
established pre-defined criteria for negative and positive studies. Further diagnostic
testing on patients with negative results will not be undertaken unless dictated by
follow-up evaluation. Patients in the observation cohorts will not be treated and therapy
will be given to all patients with positive results. Diagnostic suspicion bias will be
avoided by objectively testing all patients who return during follow-up with symptoms or
signs suggestive of deep venous thrombosis or pulmonary embolism. Interpretation bias will
be avoided by obtaining independent interpretation of follow-up testing in patients with
suspected disease. The interpreter will be blinded to the results of the initial ultrasound
and the cohort to which the patient belongs. All deaths will be independently reviewed.
The reviewer will be blinded to the cohort to which the patient belongs. Patient
confidentiality will be maintained by keeping the patient identity log separate from the
database, which will use only unique numerical identifiers. Complete data tracking will be
assured by comparison of enrollment log and database by independent reviewer.

Statistical Analysis and Sample Size

Descriptive statistics for age, sex, symptoms at presentation (pain, tenderness, duration of
symptoms), clinical conditions (recent surgery, recent hospitalization, cancer, congestive
heart failure, recent immobilization, recent childbirth, cellulitis, superficial phlebitis
and family history of thromboembolic disease) and the pre-test probability score will be
calculated to characterize the study population.

The event rate of thromboembolic complications and death from thromboembolic disease will be
calculated for patients in the two observation cohorts.

A two-sided confidence interval for the event rate (objectively verified venous
thromboembolism) will be calculated for the observation cohort by exact methods. If this
confidence interval excludes the commonly accepted threshold event rate of 3%, we will
conclude that the diagnostic strategy is clinically valid.

We will also describe the clinical characteristics of clots and other endpoints when those
data are available.

The sample size of 478 patients who meet eligibility criteria was chosen so that an exact
95% confidence interval would exclude an event rate of venous thromboembolism in the
observation cohort of 3%. Excluding an event rate of 3% is the commonly accepted standard
by which diagnostic strategies are deemed clinically acceptable.