Whole-leg Ultrasound in Pregnant Patients

SPECIFIC AIM To determine the rate of thromboembolic complications (including death
attributed to thromboembolic disease) in pregnant patients suspected of deep vein thrombosis
(DVT) when anticoagulation therapy is withheld on the basis of a negative whole-leg
compression ultrasound examination (whole-leg CUS).

BACKGROUND AND SIGNIFICANCE

The diagnosis of deep vein thrombosis of the leg is challenging due to the great variability
of clinical presentation and the lack of sensitivity of noninvasive tests. This is
particularly true for pregnant patients, who have been excluded from most major studies of
diagnostic strategies for DVT. Ironically, pregnancy is considered a major risk factor for
DVT, making evidence-based diagnosis in this patient group particularly important.

A study performed at LDS Hospital, found that a single, whole-leg compression ultrasound
could safely exclude the diagnosis of suspected, symptomatic, first-episode deep vein
thrombosis of the leg. A subsequent metanalysis of studies of the same technique confirmed
this finding, but observed that the utility of this strategy in pregnant patients required
further study, as only 57 of the over 4,500 subjects in the pooled metanalysis were pregnant.

Therefore, better information regarding the performance of diagnostic testing for suspected
DVT in pregnant patients is needed. If whole-leg compression ultrasound proves adequately
sensitive in this patient group, this will be a significant step in simplifying the
diagnostic process for deep vein thrombosis, and will confirm the diagnostic strategy most
commonly used presently by physicians at Intermountain Medical Center.

EXPERIMENTAL DESIGN AND METHODS

Design Prospective clinical cohort study ("management study").

Patients 268 sequentially-enrolled pregnant patients evaluated for suspected symptomatic deep
vein thrombosis of the leg, reporting to the Intermountain Medical Center Peripheral Vascular
Laboratory. Vascular technicians will pre-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 reason for exclusion, and provide
informed consent.

Demographic and medical history information:

Clinical information relevant to the study will be obtained from the Study Coordinator
following informed consent during the initial study interview. Query of the Intermountain
Healthcare electronic medical record will also be performed at entry. Relevant information
will be included on a standardized Case Report Form.

Informed Consent documents, Case Report Forms and relevant source documents from the
electronic medical record will be obtained, placed in a study binder and stored according to
the policies of the Institutional Review Board.

Measurements:

A research clinician will perform a brief clinical assessment, including adequate information
to calculate the LeFT clinical prediction score, which has been evaluated in a prior study.
Patients will then proceed to performance of whole-leg compression ultrasound.

Objective Testing for Venous Thrombosis Whole-leg CUS will be performed on all patients. A
standardized technique will be used for the CDU examination, which is identical to the
protocol used clinically by the Intermountain Medical Center Peripheral Vascular Laboratory.

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.

If the vascular technologist develops suspicion of isolated iliac DVT (based on absence of
phasic respiratory flow or complete absence of flow in the common femoral vein by Doppler,
but with normal compression) the referring physician and principal investigator will be
contacted immediately by telephone. Further evaluation (usually by an alternate imaging
modality) will be ordered at the discretion of the referring physician according to best
clinical judgment.

Interpretation will be performed by experienced vascular surgery staff according to protocols
currently in use at Intermountain Medical Center. Findings will be redacted to specific data
fields by the interpreting surgeon according to a form generated for this purpose, and
entered onto a Case Report Form.

Interobserver variability will be limited by using a priori criteria for a positive and
negative study. Interobserver agreement for this technique has been found to be high in a
prior study.

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

If the result of testing is abnormal (DVT identified), the patient will be referred to the
treating clinician for usual management at the discretion of the clinician. This group will
not be followed for study outcomes.

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 treating physician.

Long-Term Follow-up Patients with a negative whole-leg CUS will undergo three months of
clinical follow-up, a strategy used in many diagnostic trials for DVT.2 Patients will be
instructed to return immediately to our emergency department if they have symptoms or signs
of DVT or pulmonary embolism (PE). A study clinician will assess them at 3 months by
telephone interview using a standardized questionnaire.

If patients contact the study team with symptoms suspicious for DVT or PE, they will be
evaluated by a study clinician in the Thrombosis Clinic (symptoms of DVT), or referred to
emergent care for evaluation (symptoms of PE). Participants' treating clinicians are also
free to obtain any medically appropriate diagnostic testing for suspected DVT or PE during
the follow-up period. A letter will be sent to referring physicians explaining the protocol
and emphasizing that any appropriate diagnostic testing for suspected DVT or PE may be
performed as clinically indicated.

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. If at follow-up a patient identifies symptoms
suspicious for DVT or PE that have not previously been clinically evaluated, they will be
scheduled for an in-person evaluation with a physician in the Intermountain Medical Center
Thrombosis Clinic.

In addition to information obtained from the patient during the follow-up visit, a
comprehensive review of the patient's Intermountain electronic health record will be
performed to look for evidence of diagnostic testing for deep vein thrombosis or pulmonary
embolism or use of anticoagulant medications. Additionally, the study coordinator presently
receives alerts of all positive diagnostic tests for DVT and PE performed in the facility
daily. This list will be reviewed for study participants.

Results of the follow-up assessment will be entered on a Case Report Form by study staff.
This form will be added to the study binder by the study coordinator and information appended
to the database by the data entry clerk.

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% or greater will be
defined as clinically acceptable, in accordance with previous trials of DVT diagnosis.

The study will report analysis of outcomes both on a per-protocol and intention-to-treat
basis in the event of protocol violation (i.e. receipt of therapeutic anticoagulation despite
negative whole-leg ultrasound, without objective evidence of a thrombotic complication).

In the event of withdrawal of participation, affected subjects will be suppressed from
analysis (i.e. analysis will be performed on a per protocol basis), or in the event that
isolated iliac DVT is diagnosed following vascular technologist suspicion. Isolated iliac DVT
diagnosed after additional imaging resulting from technologist suspicion will be analyzed as
an additional outcome variable, and the rate of this diagnosis reported with a corresponding
exact 95% confidence interval. Use of intention-to-treat analysis could bias results of the
study in the case of withdrawn subjects as they would, by definition, not complete the
defined follow-up period and would not have ascertainment of the primary study outcome.

Adjudication of Outcomes A panel of three independent physicians with established expertise
in venous thromboembolism will be named to adjudicate all suspected events of DVT or PE, and
all diagnostic tests for these occurring during the follow-up period. Simple majority will
resolve disputes. All deaths will be adjudicated as to whether attributable to PE or another
cause by the same group of adjudicators.

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 new or progressive
symptoms. Patients with a negative whole-leg CUS 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 by independent adjudicators. The
adjudicators 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 adjudicators 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

Descriptive statistics for age, weight, height, trimester (weeks gestation), symptoms at
presentation (pain, tenderness, duration of symptoms), clinical conditions (recent surgery,
recent hospitalization, cancer, congestive heart failure, recent immobilization, cellulitis,
superficial phlebitis and family history of thromboembolic disease) and the LeFT variables
(including leg circumference) will be calculated to characterize the study population.

The event rate of thromboembolic complications and death from thromboembolic disease will be
calculated for patients with negative whole-leg CUS; both per-protocol and by
intention-to-treat.

The rate of isolated iliac DVT detected after vascular technologist suspicion will be
reported as a separate calculation with corresponding exct 95% confidence interval

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 (e.g. venous distribution) and
other endpoints when those data are available.

The sample size of 268 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.

Inclusion Criteria:

- Be suspected by the referring medical provider to have a first episode of acute DVT of
the lower extremities.

- Be presenting for the initial diagnostic ultrasound for the present symptom complex.

- Pregnancy confirmed by an objective test.

- Be > 18 years old.

- Provide written informed consent.

Exclusion Criteria:

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

- The patient has a prior history of DVT in the ipsilateral leg.

- Previous venous ultrasound has been performed during the same pregnancy.

- The patient is suspected by the referring clinician to have symptomatic pulmonary
embolism.

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

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

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

- Informed consent cannot be obtained.