Normal Results on D-Dimer Testing Can Safely Rule out Deep Vein Thrombosis

A simplified approach of an initial stand-alone D-dimer test followed by a single whole-leg compression ultrasound (CUS) in D-dimer positive patients can effectively and safely rule out deep vein thrombosis (DVT) in outpatients with a failure rate of <1%, a study in Blood Advances suggests.

According to the study’s lead author, Synne Fronas, MD, of the University of Oslo and the Østfold Hospital Trust in Norway, using D-dimer as the initial step and conducting a single whole-leg CUS in only patients with positive D-dimer can simplify the diagnostic workup of DVT in outpatients. “We believe it is faster, easier, and less user-dependent than including a clinical prediction model,” Dr. Fronas told ASH Clinical News when asked about the study’s testing algorithm. “On a system level, there will be fewer unnecessary ultrasound examinations because not all patients are referred – only the ones with positive D-dimer.”

Commonly, DVT evaluation consists of three elements: a pretest probability assessment, D-dimer test, and ultrasound examination of the leg. The first element, pretest probability assessment, involves checking for common signs and symptoms of DVT and risk factors. “If the patient gets a high-risk score, he or she is referred directly for ultrasound without considering D-dimer, whereas the rest of the patients only do ultrasound if D-dimer is positive,” explained Dr. Fronas. “In our study, we omitted the first item of clinical pretest probability assessment and used D-dimer as the sole test to decide whether the patient should be referred for ultrasound. Patients with positive D-dimer were referred, whereas patients with negative D-dimer were not.”

The Rivaroxaban for Scheduled Work-up of DVT (Ri-Schedule) study, which was designed to assess the safety of rivaroxaban in the pre-diagnosis phase of DVT, included 1,397 consecutive outpatients who were referred from primary care to the emergency department at a hospital in Norway between 2015 and 2018 for suspected first or recurrent DVT. All participants underwent D-dimer testing.

“We believe [initial D-dimer testing] is faster, easier, and less user-dependent than including a clinical prediction model.”

—Synne Fronas, MD

A total of 982 patients (70.3%) had a positive D-dimer, defined as D-dimer levels of ≥0.5 mcg/mL fibrinogen-equivalent units, and were referred for whole-leg CUS. Patients with negative D-dimer (n=415; 29.7%) and no or negative CUS were subsequently followed for up to 3 months to assess the rate of venous thromboembolism (VTE).

The failure rate of stand-alone D-dimer testing (the study’s primary endpoint) was defined as the proportion of patients with a baseline negative D-dimer level who developed VTE or died of an unknown cause that was possibly related to VTE within 3 months of follow-up. The failure rate of whole-leg CUS was defined as the proportion of patients with normal baseline CUS who developed VTE or died of an unknown cause that was possibly related to VTE within the 3-month follow-up period.

The median age of the patient population was 64 years, and 55% of the patients were women. Overall, patients had a median symptom duration of 7 days. A diagnosis of DVT was made in 277 patients (19.8%).

Six patients in whom DVT was ruled out at baseline because of a negative D-dimer and/or normal CUS were diagnosed with DVT within the 3-month follow-up period, corresponding to a failure rate of 0.5%.

Looking at the stand-alone D-dimer test, three of the 415 patients with negative D-dimer at baseline received a DVT diagnosis, representing a failure rate of 0.7% for the D-dimer stand-alone test. Among the 698 patients with a normal CUS at baseline, three were diagnosed with DVT during the next 3 months, corresponding to a failure rate of 0.4%.

Forty-three patients underwent CUS despite a negative D-dimer at baseline, which was most often related to strong suspicion of DVT due to specific symptoms or signs. “In the event of low [clinical pretest probability], physicians might be more inclined not to refer the patient for CUS despite positive D-dimer, or to dismiss an uncertain radiologic finding,” Dr. Fronas and coauthors wrote. “However, when performed correctly, falsely interpreted CUS examinations for first DVT are rare.”

Limitations of this study included its single-center design and the inclusion of only outpatients, which the investigators suggest could limit the generalizability of the findings to other settings, such as the emergency department or inpatient hospital. The researchers also used only one D-dimer assay, which limits generalizability across other assays, including point-of-care devices.

Study authors report relationships with Bayer, which sponsored this trial.

Reference

Fronas SG, Jørgensen CT, Dahm AEA, et al. Safety of a strategy combining D-dimer testing and whole-leg ultrasonography to rule out deep vein thrombosis. Blood Adv. 2020;4(20):5002-5010.