By Susan L. Taylor, MS, MT (ASCP), MBA

In September 2003, the VIDAS® D-Dimer New™ from bioMerieux was approved by the United States Food and Drug Administration (FDA) for use in excluding a diagnosis of deep-vein thrombosis (DVT) when used in conjunction with a pre-test probability model (Figure 1) and to aid in the diagnosis of pulmonary embolism (PE) in outpatients. It is the first D-dimer assay to be marketed for exclusion of DVT and it has been evaluated for safety and efficacy in more than 50 peer-reviewed reference articles, reporting on more than 10,000 patients. A negative result, returned from the laboratory in less than 1 hour, can quickly allow a physician to exclude a diagnosis of DVT or PE without waiting for costly and time-consuming imaging studies that often provide indefinite or inconclusive results.

Unit-dose format provides ease-of-use and reliable results.

Developments in D-dimer assays over the past 4 years have provided clinicians with rapid and automated test results for emergency patients and outpatients suspected of having DVT or PE. However, until now, no D-dimer assays have been cleared for use in ruling out these potentially life-threatening conditions that occur in millions of patients per year.¹ Since 1998, bioMerieux has offered a highly sensitive VIDAS D-Dimer assay for screening patients suspected of having DVT or PE. Last year, bioMerieux validated and the FDA cleared an extended-range version of the assay to expand its clinical utility to include diagnosis and monitoring of disseminated intravascular coagulation (DIC), without the need to dilute and re-run samples with very high results. The renamed product, VIDAS D-Dimer New, maintained the simple, ready-to-use, unit-dose, ELISA method, but increased the upper limit of the reportable range from 1,000 ng/mL to 10,000 ng/mL. The latest FDA-cleared VIDAS D-Dimer New for exclusion of DVT improves patient care by reducing exposure to invasive procedures, eliminating unnecessary anticoagulant treatment, reducing costs, and shortening the patient’s length of stay in the emergency department.

Small footprint VIDAS immunoassay analyzer provides STAT results, 24 hours a day, 7 days a week.

Background
More than six million Americans per year present to physicians with symptoms of DVT and PE, two conditions collectively referred to as venous thromboembolism (VTE).1 DVT occurs when a fibrin clot forms in one of the large veins, usually in a lower limb, leading to either partially or completely blocked circulation. Common risk factors for DVT include conditions in which a person has been immobile, such as lengthy illness, recent surgery, trauma, or long-distance travel. Additional risk factors include malignancy, pregnancy, oral contraceptive use, and genetic predisposition. The most severe and common life-threatening consequence of DVT is PE. A PE occurs when either the clot or a piece of the clot breaks loose and travels to the lung where it lodges in a vein and causes cardiopulmonary stress. This stress is often manifested by shortness of breath and pain upon inspiration and can be immediately fatal.

Occasionally, symptoms of PE are the first indication that a patient has had a DVT. Too often, PE is diagnosed at autopsy. Approximately 200,000 cases of PE are diagnosed each year in the United States. Each case carries a 20% risk of sudden death; therefore, rapid diagnosis and early treatment of DVT are critical to preventing subsequent morbidity and death.² It is also imperative to exclude the diagnosis of DVT in patients without the condition, because there is an inherent risk of hemorrhage associated with unnecessary anticoagulant treatment, which may be prescribed in these cases.

As most emergency department physicians will attest, clinical evaluation of a patient in whom DVT is suspected presents a diagnostic challenge. The diagnosis cannot be based on clinical grounds alone, because symptoms vary from patient to patient. Symptoms of DVT are nonspecific and include swelling, tenderness, and pain. The only conclusive test to diagnose DVT or PE is venography, a radio-imaging study in which contrast dye is injected into the venous system and blood flow is visualized. Because venography is invasive and costly, and it carries its own inherent risks, these studies are reserved for patients most likely to have a DVT or PE. Non-invasive imaging studies, such as ultrasonography, spiral-computed tomography, and ventilation perfusion scans may be used in less suspicious cases but do not provide a diagnostic result unless the clot is actually visualized. Because up to 75% of patients suspected of having VTE will not have the condition and the non-invasive imaging studies are likely to return inconclusive results, expensive and time-consuming serial testing may be required.1 Thus, diagnosis of DVT could be delayed, putting a positive patient at risk of being sent home without appropriate treatment and of developing a potentially fatal PE.

Fortunately, with VIDAS D-Dimer New, the laboratory can meet the diagnostic challenge presented by DVT. Multiple prospective management studies using VIDAS D-Dimer, an indirect indicator of clot formation, have proven that quantitative D-dimer assay results can safely exclude a diagnosis of VTE in outpatients.1 D-dimer, a component of a cross-linked fibrin clot, is released into the circulatory system during the process of clot breakdown. As part of the body’s protective hemostatic balance, cross-linked fibrin clots are formed in response to vessel injury. At the same time, activation of the clot breakdown mechanism is triggered, and resulting D-dimer molecules are released into the circulation. Therefore, normal levels of D-dimer, determined with an appropriately sensitive method, have been established as a safe and effective means of excluding the presence of DVT when it is suspected in outpatients.

The VIDAS D-DImer New assay is performed on bio Merieux’s VIDAS immunoassay analyzers.

Because so many patients who present with symptoms of VTE do not actually have the condition, there is significant benefit to patient care and labor and cost management if the diagnosis is quickly ruled out, particularly for patients with a low or moderate clinical pretest probability. As proven in the first prospective management study (Lancet), a negative VIDAS D-Dimer assay result with a pretest probability assessment is all that is required to exclude DVT. Further diagnostic tests, such as compression ultrasonography, spiral-computed tomography, ventilation perfusion scanning, and contrast venography, are not needed. These tests are often painful, expensive, and potentially risky. VIDAS D-Dimer New allows clinical laboratorians to provide physicians with a safe, cost-effective, time-sensitive result to rule out DVT.

Clinical Performance
A negative VIDAS D-Dimer New result carries significant diagnostic utility, particularly for exclusion of DVT. However, an abnormal D-dimer result is not an indicator of any specific clinical condition. Results can be abnormal in cases of malignancy, chronic illness, pregnancy, trauma, and DIC, to name a few. Therefore, it is critical, when evaluating the performance of a D-dimer assay, to understand the concepts of clinical sensitivity and negative predictive value (NPV). Clinical sensitivity, the probability that a patient with the disease will have a positive test result, is affected by false-negative results. That is, given 100 patients, each 1% decrease from 100% reflects one false-negative result (clinical sensitivity [%] = [TP/(TP + FN)] x 100, where TP = true positive and FN = false negative). NPV is an indication of the ability of the assay to rule out the disease (NPV [%] = [TN/(TN + FN)] x 100). It is also negatively affected by false-negative results. These indicators should be very close to 100%. Additionally, the D-dimer assay should have sufficient clinical specificity— the ability to correctly identify patients who do not have the disease—in order to avoid unnecessary work-ups (clinical specificity [%] = [TN/(TN + FP)] x 100).

VIDAS D-Dimer New performs consistently, returning clinical sensitivities and NPVs greater than 99% for exclusion of DVT in patients with low, moderate, and high pretest probability as well as in patients suspected of PE.^3,4,5 If the sensitivity and NPV are not at or near 100%, a diagnosis of DVT or PE could be missed because of a false-negative D-dimer result and the patient would not be treated, a potentially fatal error.

Analytical Performance
Enzyme-linked immunosorbent assay (ELISA) methods are typically referred to as “the gold standard” of D-dimer assays. Known for their high levels of performance, the classical ELISA methods are extremely laborious and time-consuming. VIDAS D-Dimer New combines the gold-standard performance of the ELISA method with a rapid, easy-to-use, unit-dose format that produces safe and reliable D-dimer results in 35 minutes. The assay is performed on bioMérieux’s miniVIDAS immunoassay analyzer, a small-footprint instrument well suited for any lab environment including a STAT lab; or on the larger, higher-throughput, VIDAS 30 immunoassay analyzer. Once 200 µL of plasma is transferred to the test strip, the strip is placed on the instrument and requires no more attention until the result is reported 35 minutes later. The simplicity of the test procedure makes it ideal for 24-hour, 7-day availability.

VIDAS D-Dimer New features a coefficient of variation (CV%), an indication of the precision of the assay or reproducibility of results, of less than 5% at the clinical decision point for VTE of 500 ng/mL.⁶ In fact, VIDAS D-Dimer New is the only D-dimer assay on the market to include a cut-off value in its package insert, although it is recommended that each laboratory establish its own reference value.

VIDAS D-Dimer New also offers clinicians an extended reportable range – from 45 ng/mL to 10,000 ng/mL – enabling detection and monitoring of high levels of D-dimer that are clinically significant in conditions such as DIC. The broad reportable range of VIDAS D-Dimer New eliminates the need for dilution of samples with D-dimer concentrations above 1,000 ng/mL. This time-consuming process requires additional labor, delays the result, and introduces additional opportunities for error.

VIDAS D-Dimer New is not affected by interfering substances that can affect automated latex assays such as those for lipemia, bilirubinemia, rheumatoid factor, or hemolysis.6 Automated latex assays are homogeneous, that is, performed in one cuvette or reaction vessel. The patient sample and reagents are all added to the same vessel in which the reaction proceeds to completion. The endpoint is read optically by turbidimetry; thus, any turbid or colored artifacts in the sample can artificially impact the results because they will alter the amount of light that is absorbed or transmitted by the mixture. Because VIDAS D-Dimer New is heterogeneous, that is, performed in a series of test wells and includes multiple washing steps, lipemia, turbidity, and other interfering conditions are eliminated before the final fluorescent readings are taken. Only the D-dimer molecules and reagents required to complete the reaction are left in the cuvette where the optical readings take place, providing for accurate and reliable results.

Cost Savings
VIDAS D-Dimer New can significantly reduce a hospital’s overhead costs. According to a study conducted by Piedmont Hospital in Atlanta, the use of the VIDAS D-Dimer assay saved the hospital more than $688,000 per year, or $1,368 per patient, just by eliminating unnecessary imaging studies for outpatients suspected of having VTE.⁷ Additional cost savings, although not documented, were likely realized by moving those patients through the emergency department more quickly and avoiding unnecessary anticoagulant treatment.

Laboratories that have included VIDAS D-Dimer New on their test menus, and emergency departments that have included these results in their diagnostic algorithms for DVT and PE have improved patient care and their institution’s bottom line.

For additional information, contact Susan L. Taylor, MS, MT(ASCP), MBA, Marketing Manager, Hemostasis, bioMerieux Inc, Durham, NC 27712; (919) 620-2420; susan.taylor@na.biomerieux.com.

References
1. Perrier A, et al. Non-invasive diagnosis of venous thromboembolism in outpatients. Lancet. 1999; 353:190-195.
2. Heit J, et al. The epidemiology of venous thromboembolism in the community. Thromb Haemost. 2001; 86:452-463.
3. Bates S, et al. A diagnostic strategy involving a quantitative latex D-dimer assay reliably excludes deep venous thrombosis. Ann Intern Med. 2003; 138:787-794.
4. De Moerloose P, et al. Performances of the VIDAS D-Dimer New assay for the exclusion of venous thromboembolism, Thromb Haemost. 2001; 85:185-186.
5. Wells P, et al. Value of assessment of pre-test probability of deep-vein thrombosis in clinical management. Lancet. 1997; 350:1795-1798.
6. VIDAS D-Dimer New package insert, no. 008120-4, rev. 2003/09.
7. Beltran S, et al. Economic Study, Piedmont Hospital, Atlanta, 2001.

VIDAS is a registered trademark and D-Dimer New is a trademark of bioMérieux Inc.