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Original Research |

Selective d-Dimer Testing for Diagnosis of a First Suspected Episode of Deep Venous Thrombosis: A Randomized Trial

Lori-Ann Linkins, MD; Shannon M. Bates, MDCM; Eddy Lang, MDCM; Susan R. Kahn, MD; James D. Douketis, MD; Jim Julian, MMath; Sameer Parpia, PhD; Peter Gross, MD; Jeffrey I. Weitz, MD; Frederick A. Spencer, MD; Agnes Y.Y. Lee, MD; Martin J. O'Donnell, PhD; Mark A. Crowther, MD; Howard H. Chan, MD; Wendy Lim, MD; Sam Schulman, MD; Jeffrey S. Ginsberg, MD; and Clive Kearon, MD
[+] Article and Author Information

From McMaster University, Hamilton, Ontario, Canada; University of Calgary, Calgary, Alberta; McGill University, Montreal, Québec, Canada; University of British Columbia, Vancouver, British Columbia, Canada; and HRB-Clinical Research Facility, National University of Ireland, Galway, Ireland.

Disclaimer: Dr. Linkins had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Acknowledgment: The authors thank Diagnostica Stago and bioMérieux for providing the d-dimer assays used for this research. The authors thank Sue Smale; Pam Stevens, RN; Laurie Sardo, RN; Carla Strulovitch, RN; David Morrison, MSc; Chris Tselios, IMG; Yanka Mihaylova, IMG; Antoinette Colacone, BSc, CCRA; Tanya Castelino, MD; and Lisa Rudd-Scott, RN, for enrolling patients. They also thank Clare Stewart, Donna McCarthy, and Nanci Howat for study coordination; Jack Hirsh, MD, and Mark Levine, MD, for study adjudication; Robin Roberts, MSc, for conducting the data safety reviews; and all patients who participated in the study.

Grant Support: By the Heart and Stroke Foundation of Ontario (T-6392). Dr. Linkins is a recipient of a New Investigator Award from the Heart and Stroke Foundation of Canada. Dr. Kahn is a recipient of a National Research Scientist Award from the Fonds de la Recherche en Santé du Québec. Dr. Douketis is a recipient of the GlaxoSmithKline Distinguished Scholar Award in Thrombosis from the Chest Foundation. Dr. Weitz is the recipient of the Canada Research Chair (Tier 1) in Thrombosis and the Heart and Stroke Foundation of Ontario and J. Fraser Mustard Chair in Cardiovascular Research. Dr. Spencer is a recipient of an Investigator Award from the Heart and Stroke Foundation of Canada. Dr. Crowther holds the Leo Pharma Chair in Thromboembolism Research at McMaster University and is a Career Investigator of the Heart and Stroke Foundation of Ontario. Dr. Lim is the recipient of the E.J. Moran Campbell Internal Career Award from McMaster University. Dr. Ginsberg is a recipient of a Career Investigator Award of the Heart and Stroke Foundation of Ontario and the David Braley and Nancy Gordon Chair for investigation of thromboembolic diseases. Dr. Kearon is a recipient of a Career Investigator Award from the Heart and Stroke Foundation of Ontario.

Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M12-1158.

Reproducible Research Statement: Study protocol: Available from Dr. Linkins (e-mail, linkinla@mcmaster.ca). Statistical code: Not available. Data set: For access to the database, submit study objectives and planned analyses to Dr. Linkins (e-mail, linkinla@mcmaster.ca).

Requests for Single Reprints: Lori-Ann Linkins, MD, Department of Medicine, McMaster University, Juravinski Hospital, Room A3-74, 1280 Main Street West, Hamilton, Ontario L8S 4K1, Canada; e-mail, linkinla@mcmaster.ca.

Current Author Addresses: Dr. Linkins: Department of Medicine, McMaster University, Juravinski Hospital, Room A3-74, 1280 Main Street West, Hamilton, Ontario L8S 4K1, Canada.

Dr. Bates: Department of Medicine, McMaster University, 1280 Main Street West, HSC, Room 3W11, Hamilton, Ontario L8S 4K1, Canada.

Dr. Lang: Department of Family Medicine, University of Calgary, 1632 14 Avenue NW, Calgary, Alberta T2N 1M7, Canada.

Dr. Kahn: Department of Medicine, McGill University, Jewish General Hospital, 3755 Côte Sainte Catherine Road, Room H-420, Montreal, Québec H3T 1E2, Canada.

Dr. Douketis: Department of Medicine, St. Joseph's Healthcare, Fontbonne Building, F:544, 50 Charlton Ave East, Hamilton, Ontario L8N 4A6, Canada.

Mr. Julian and Dr. Parpia: Ontario Clinical Oncology Group, 711 Concession Street, G Wing, 1st Floor, Room 101, Hamilton, Ontario L8V 1C3, Canada.

Dr. Gross: Department of Medicine, 1280 Main Street West, McMaster University, Hamilton General Site, DBCVSRI, Room C5-119, Hamilton, Ontario L8S 4K1, Canada.

Dr. Weitz: Department of Medicine, 1280 Main Street West, McMaster University, Hamilton General Site, DBCVSRI, Room C5-123, Hamilton, Ontario L8S 4K1, Canada.

Dr. Spencer: Department of Cardiology, St. Joseph's Healthcare, Martha Wing, H329, 50 Charlton Avenue East, Hamilton, Ontario L8N 4A6, Canada.

Dr. Lee: Department of Medicine, University of British Columbia, Vancouver General Hospital, Gordon & Leslie Diamond Health Care Centre, 2775 Laurel Street, Vancouver, British Columbia V5Z 1M9, Canada.

Dr. O'Donnell: Department of Medicine, HRB-Clinical Research Facility, National University of Ireland, Galway, Geata an Eolais, University Road, Galway, Ireland.

Dr. Crowther: Department of Medicine, St. Joseph's Healthcare, Martha Wing, L301-3, 50 Charlton Avenue East, Hamilton, Ontario L8N 4A6, Canada.

Dr. Chan: Department of Medicine, 1280 Main Street West, McMaster University, Hamilton General Site, DBCVSRI, Room C4-122, Hamilton, Ontario L8S 4K1, Canada.

Dr. Lim: Department of Medicine, St. Joseph's Healthcare, Room L208, 50 Charlton Avenue East, Hamilton, Ontario L8N 4A6, Canada.

Dr. Schulman: Department of Medicine, 1280 Main Street West, McMaster University, Hamilton General Site, McMaster Clinic, Room 611, Hamilton, Ontario L8S 4K1, Canada.

Dr. Ginsberg: Department of Medicine, St. Joseph's Healthcare, Martha Wing, H318, 50 Charlton Avenue East, Hamilton, Ontario L8N 4A6, Canada.

Dr. Kearon: Department of Medicine, McMaster University, 1280 Main Street West, Juravinski Hospital, Room A3-73, Hamilton, Ontario L8S 4K1, Canada.

Author Contributions: Conception and design: L.A. Linkins, S.M. Bates, S.R. Kahn, J. Julian, J.I. Weitz, M.A. Crowther, J.S. Ginsberg, C. Kearon.

Analysis and interpretation of the data: L.A. Linkins, E. Lang, J.D. Douketis, J. Julian, S. Parpia, J.I. Weitz, C. Kearon.

Drafting of the article: L.A. Linkins, J. Julian, S. Parpia, J.I. Weitz, M.A. Crowther, J.S. Ginsberg.

Critical revision of the article for important intellectual content: L.A. Linkins, S.M. Bates, E. Lang, S.R. Kahn, J. Julian, J.D. Douketis, S. Parpia, P. Gross, J.I. Weitz, F.A. Spencer, A.Y.Y. Lee, H.H. Chan, S. Schulman, J.S. Ginsberg, C. Kearon.

Final approval of the article: L.A. Linkins, S.M. Bates, E. Lang, S.R. Kahn, J. Julian, J.D. Douketis, S. Parpia, P. Gross, J.I. Weitz, F.A. Spencer, A.Y.Y. Lee, M.J. O'Donnell, W. Lim, S. Schulman, J.S. Ginsberg, C. Kearon.

Provision of study materials or patients: L.A. Linkins, S.M. Bates, S.R. Kahn, J.D. Douketis, P. Gross, A.Y.Y. Lee, M.J. O'Donnell, H.H. Chan, W. Lim, S. Schulman, J.S. Ginsberg, C. Kearon.

Statistical expertise: J. Julian, S. Parpia.

Obtaining of funding: L.A. Linkins, S. Schulman, J.S. Ginsberg, C. Kearon.

Administrative, technical, or logistic support: M.J. O'Donnell, M.A. Crowther, S. Schulman, C. Kearon.

Collection and assembly of data: L.A. Linkins, S.M. Bates, E. Lang, S.R. Kahn, S. Parpia, P. Gross, M.J. O'Donnell, S. Schulman, C. Kearon.


Ann Intern Med. 2013;158(2):93-100. doi:10.7326/0003-4819-158-2-201301150-00003
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Chinese translation

Background: d-Dimer testing is sensitive but not specific for diagnosing deep venous thrombosis (DVT). Changing the use of testing and the threshold level for a positive test result on the basis of risk for DVT might improve the tradeoff between sensitivity and specificity and reduce the need for testing.

Objective: To determine whether using a selective d-dimer testing strategy based on clinical pretest probability (C-PTP) for DVT is safe and reduces diagnostic testing compared with using a single d-dimer threshold for all patients.

Design: Randomized, multicenter, controlled trial. Patients were allocated using a central automated system. Ultrasonographers and study adjudicators but not other study personnel were blinded to trial allocation. (ClinicalTrials.gov: NCT00157677)

Setting: 5 Canadian hospitals.

Patients: Consecutive symptomatic patients with a first episode of suspected DVT.

Intervention: Selective testing (n = 860), defined as d-dimer testing for outpatients with low or moderate C-PTP (DVT excluded at d-dimer levels <1.0 µg/mL [low C-PTP] or <0.5 µg/mL [moderate C-PTP]) and venous ultrasonography without d-dimer testing for outpatients with high C-PTP and inpatients, or uniform testing (n = 863), defined as d-dimer testing for all participants (DVT excluded at d-dimer levels <0.5 µg/mL).

Measurements: The proportion of patients not diagnosed with DVT during initial testing who had symptomatic venous thromboembolism during 3-month follow-up and the proportion of patients undergoing d-dimer testing and ultrasonography.

Results: The incidence of symptomatic venous thromboembolism at 3 months was 0.5% in both study groups (difference, 0.0 percentage point [95% CI, −0.8 to 0.8 percentage points]). Selective testing reduced the proportion of patients who required d-dimer testing by 21.8 percentage points (CI, 19.1 to 24.8 percentage points). It reduced the proportion who required ultrasonography by 7.6 percentage points (CI, 2.9 to 12.2 percentage points) overall and by 21.0 percentage points (CI, 14.2 to 27.6 percentage points) in outpatients with low C-PTP.

Limitation: Results may not be generalizable to all d-dimer assays or patients with previous DVT, study personnel were not blinded, and the trial was stopped prematurely.

Conclusion: A selective d-dimer testing strategy seems as safe as and more efficient than having everyone undergo d-dimer testing when diagnosing a first episode of suspected DVT.

Primary Funding Source: Heart and Stroke Foundation of Ontario.

Figures

Grahic Jump Location
Appendix Figure 1.

Study flow diagram.

DVT = deep venous thrombosis; PE = pulmonary embolism.

* Patients may have met >1 exclusion criteria.

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Grahic Jump Location
Figure.

Results according to randomly assigned study group.

For the uniform testing group, of the 4 patients who did not have d-dimer testing and another patient with a d-dimer–positive result who did not have ultrasonography, 4 had no events during follow-up and 1 with a d-dimer–negative result was lost to follow-up. For the selective testing group, neither of the 2 patients who did not have d-dimer testing during initial testing had an event during follow-up. C-PTP = clinical pretest probability; DVT = deep venous thrombosis; VTE = venous thromboembolism.

* 1 patient lost to follow-up.

† 3 recurrent VTEs during follow-up.

‡ 1 recurrent VTE during follow-up.

Grahic Jump Location
Grahic Jump Location
Appendix Figure 2.

Results for the uniform testing group, according to C-PTP.

C-PTP = clinical pretest probability; DVT = deep venous thrombosis; VTE = venous thromboembolism.

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