International, multicenter evaluation of a new D-dimer assay for the exclusion of venous thromboembolism using standard and age-adjusted cut-offs

doi:10.1016/j.thromres.2018.04.003

Thrombosis Research

Volume 166, June 2018, Pages 63-70

https://doi.org/10.1016/j.thromres.2018.04.003 Get rights and content

Highlights

•
The INNOVANCE D-dimer is highly sensitive; PE and DVT can be excluded by D-Dimer.
•
Age-adjusting D-dimer allows more patients to be safely excluded for PE and DVT.
•
More PE and DVTs are missed as you increase the age-adjustment threshold.

Abstract

Introduction

We sought to determine the test characteristics of an automated INNOVANCE D-dimer assay for the exclusion of pulmonary embolism (PE) and deep venous thrombosis (DVT) in emergency department (ED) patients using standard and age-adjusted cut-offs.

Methods

Cross-sectional, international, multicenter study of consecutive patients with suspected DVT or PE in 24 centers (18 USA, 6 Europe). Evaluated patients had low or intermediate Wells PE or DVT scores. For the standard cut-off, a D-dimer result <500 ng/ml was negative. For the age adjusted cut-off, we used the formula: Age (years) ∗ 10. The diagnostic standard was imaging demonstrating PE or DVT within 3 months. We calculated test characteristics using standard methods. We also explored modifications of the age adjustment multiplier.

Results

We included 3837 patients and excluded 251. The mean age of patients evaluated for PE (n = 1834) was 48 ± 16 years, with 676 (37%) male, and 1081 (59%) white. The mean age of evaluated for DVT (n = 1752) was 53 ± 16 years, with 710 (41%) male, and 1172 (67%) white. D-dimer test characteristics for PE were: sensitivity 98.0%, specificity 55.4%, negative predictive value (NPV) 99.8%, positive predictive value (PPV) 11.4%, and for DVT were: sensitivity 92.0%, specificity 44.8%, NPV 98.8%, PPV 10.3%. Age adjustment increased specificity (59.6% [PE], 51.1% [DVT]), but increasing the age-adjustment multiplier decreased sensitivity without increasing specificity.

Conclusions

INNOVANCE D-dimer is highly sensitive and can exclude PE and DVT in ED patients with low- and intermediate- pre-test probability. Age-adjustment increases specificity, without increasing false negatives.

Introduction

D-dimer testing is the standard of care for ruling out pulmonary embolism (PE) or deep vein thrombosis (DVT) in emergency department (ED) patients with a non-high pretest probability [1] and acceptance criteria for sensitivity and negative predictive value (NPV) to exclude venous thromboembolism have been provided (CLSI Guideline H59-A). The sensitivity of the most commonly used quantitative assays is approximately 95%, which typically results in a negative predictive value (NPV) of 99%–100% [2]. Therefore, a negative D-dimer can safely rule out PE or first event of proximal DVT in patients with low or intermediate pre-test probability (e.g. Wells PE score <6 or DVT score <2) [1,[3], [4], [5], [6], [7]]. D-Dimer testing may not be sufficient to exclude recurrent DVT [8,9].

The clinical utility of D-dimer testing is limited by the test's low specificity, which is typically 35%–55% [2]. Many patients have false positive results, and must then undergo imaging with computed tomography pulmonary angiography (CTPA) to rule out PE or venous ultrasound (US) to rule out DVT. D-dimer testing is particularly problematic in certain patient populations with a high likelihood of positive D-dimer results [10]. These include pregnant patients, post-operative surgery patients, and the elderly, among other groups. For example, only about 10% of patients >80 years old have a negative D-dimer [11]. To improve the specificity of D-dimer testing in older patients, authors have proposed upwardly adjusting the cut-off used to define a positive test. The most commonly used formula is: Age × 10 = Cut-off. This formula has been validated in several studies including a prospective clinical trial [12]. However, factors that increase D-dimer levels also increase the risk of PE, and some studies question the safety of increasing the D-dimer cut-off for patients at higher risk of PE [10]. In addition, some studies suggest that age adjustment does not significantly decrease the false positive rate [13].

To clarify the optimal approach to D-dimer testing in the ED, we performed a cross-sectional, multi-center study of patients evaluated for PE and DVT, and determined the test characteristics of two widely available D-dimer assays using both standard and age-adjusted cutoffs.

Section snippets

Setting & ethics approval

We performed a cross-sectional, observational study of consecutive ED patients with suspected DVT or PE in 24 centers (18 USA, 6 Europe). All enrolling centers were required to have access to diagnostic testing for VTE on site, including vascular imaging: computed tomography pulmonary angiography (CTPA), ventilation/perfusion (V/Q) scanning, venous ultrasound, or peripheral venography. Centers also were required to have clinical D-dimer testing, approved for the exclusion of VTE, available on

Results

We included 3837 patients. We excluded 251 subjects. Reasons for exclusion are as follows: subject met protocol or sample exclusion criteria (N = 105), subjects in whom no sample was obtained or the sample was lost during storage (N = 120), subjects who withdrew consent (N = 4), subjects who were previously included (N = 9) or subjects who were included after study cohort enrolment had closed (N = 13). We evaluated 3586 were evaluated for PE (n = 1834) or DVT (n = 1752) [Fig. 1]. As shown in

Discussion

We performed a large, cross-sectional international study of D-dimer testing in patients suspected of having PE or DVT by their treating clinician in the ED. Included patients, therefore, represent the exact population for which D-dimer testing is indicated. We found the INNOVANCE D-dimer assay to be highly sensitive (98%), with negative predictive value near 100% and specificity >55%. These test characteristics are similar those of the VIDAS D-dimer, which was tested concurrently, and may be

Conclusions

D-dimer testing with the INNOVANCE assay is highly sensitive and can be used to exclude PE and first event of proximal DVT in emergency department patients with low- and intermediate- pre-test probability. Adjusting the cut-off of the D-dimer based on age maintains the high sensitivity and negative predictive value of the test, but may not result in a large increase in the proportion of patients who can have VTE excluded based on D-dimer testing alone.

Funding

This work was supported by Siemens Healthcare Diagnostics, Inc (protocol #: SIEM-7205).

Acknowledgements

The authors wish to thank Drs. Uwe–Peter Schobel and Thomas Wissel from Siemens Healthcare Diagnostics Products GmbH (Marburg, Germany).

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Full Length ArticleInternational, multicenter evaluation of a new D-dimer assay for the exclusion of venous thromboembolism using standard and age-adjusted cut-offs

Highlights

Abstract

Introduction

Methods

Results

Conclusions

Introduction

Section snippets

Setting & ethics approval

Results

Discussion

Conclusions

Funding

Acknowledgements

Ann. Emerg. Med.

Blood Rev.

J. Thromb. Haemost.

Chest

Dis. Mon.

J. Thromb. Haemost.

2014 ESC Guidelines on the diagnosis and management of acute pulmonary embolism

Eur. Heart J.

D-dimer for the exclusion of acute venous thrombosis and pulmonary embolism: a systematic review

Ann. Intern. Med.

Evaluation of patients with suspected acute pulmonary embolism: best practice advice from the Clinical Guidelines Committee of the American College of Physicians

Ann. Intern. Med.

Management of massive and submassive pulmonary embolism, iliofemoral deep vein thrombosis, and chronic thromboembolic pulmonary hypertension

Circulation

Full Length Article
International, multicenter evaluation of a new D-dimer assay for the exclusion of venous thromboembolism using standard and age-adjusted cut-offs