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Patient-Level Meta-analysis: Effect of Measurement Timing, Threshold, and Patient Age on Ability of d-Dimer Testing to Assess Recurrence Risk After Unprovoked Venous Thromboembolism

James Douketis, MD; Alberto Tosetto, MD; Maura Marcucci, MD; Trevor Baglin, MD, PhD; Mary Cushman, MD, MSc; Sabine Eichinger, MD; Gualtiero Palareti, MD, PhD; Daniela Poli, MD; R. Campbell Tait, MBChB; and Alfonso Iorio, MD
[+] Article and Author Information

From McMaster University, Hamilton, Ontario, Canada; S. Bortolo Hospital, Vicenza, Italy; University of Perugia, Perugia, Italy; Addenbrooke's Hospital, Cambridge, United Kingdom; University of Vermont, Burlington, Vermont; Medical University of Vienna, Vienna, Austria; University Hospital S. Orsola-Malpighi, Bologna, Italy; Azienda Ospedaliero-Universitaria Careggi, Florence, Italy; and Royal Infirmary, Glasgow, United Kingdom.


Acknowledgment: The authors thank Dr. Clive Kearon for his review of the manuscript.

Grant Support: The source studies were funded by the FCSA (Italian Federation of Anticoagulation Clinics); Oesterreichische Nationalbank (Jubilaeumsfonds); Medizinisch-Wissenschaftlicher Fonds des Buergermeisters der Bundeshauptstadt Wien; Wiener Staedtische Versicherung; Scottish Government Health Department (Chief Scientist grant CZB/4/24); and the National Heart, Lung, and Blood Institute (grants HL-57951 and HL-58036).

Potential Conflicts of Interest: Dr. Tosetto: Travel/accommodations/meeting expenses unrelated to activities listed: NovoNordisk, Instrumentation Laboratories. Dr. Cushman: Grants received: National Heart, Lung, and Blood Institute. Dr. Eichinger: Payment for lectures, including service on speakers bureaus: Boehringer Ingelheim, Bayer, Siemens Healthcare, Pfizer. Dr. Palareti: Grants received (to institution): FCSA (Italian Federation of Anticoagulation Clinics). Payment for lectures, including service on speakers bureaus: Instrumentation Laboratory, Siemens, Bayer, Sanofi-Aventis, Boehringer Ingelheim. Dr. Tait: Grants received (to institution): Scottish Government Health Department. Dr. Iorio: Board membership: Pfizer, Baxter, NovoNordisk. Consultancy: Pfizer. Payment for lectures, including service on speakers bureaus: Pfizer, Baxter, Bayer, NovoNordisk. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M10-0798.

Requests for Single Reprints: James Douketis, MD, St. Joseph's Healthcare Hamilton, Room F-544, 50 Charlton Avenue East, Hamilton, Ontario L8N 4A6, Canada; e-mail, jdouket@mcmaster.ca.

Current Author Addresses: Dr. Douketis: St. Joseph's Healthcare Hamilton, 50 Charlton Avenue East, Hamilton, Ontario L8N 4A6, Canada.

Dr. Tosetto: Division of Hematology, Ospedale San Bortolo, via Rodolfi 37, 36100 Vicenza, Italy.

Dr. Marcucci: Department of Medicine, University of Perugia, via Dottori 1, 06156 Perugia, Italy.

Dr. Baglin: Cambridge University Hospitals National Health Service Trust, Department of Haematology, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom.

Dr. Cushman: Department of Medicine, University of Vermont, 208 South Park Drive, Colchester, VT 05446.

Dr. Eichinger: Department of Medicine I, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria.

Dr. Palareti: Department of Angiology and Blood Coagulation, University Hospital of Bologna, Bologna, Italy.

Dr. Poli: Department of Heart and Vessels, Centro di Riferimento Regionale per la Trombosi, Azienda Ospedaliero-Universitaria Careggi, via le Morgagni 85, 50134 Florence, Italy.

Dr. Tait: Department of Haematology, Macewen Building, 3rd Floor, Royal Infirmary, Castle Street, Glasgow G4 0SF, United Kingdom.

Dr. Iorio: Departments of Clinical Epidemiology and Biostatistics and Medicine, McMaster University, 1200 Main Street West, Hamilton, Ontario L8N 3Z5, Canada.

Author Contributions: Conception and design: J. Douketis, A. Tosetto, M. Cushman, S. Eichinger, A. Iorio.

Analysis and interpretation of the data: J. Douketis, A. Tosetto, M. Marcucci, T. Baglin, S. Eichinger, A. Iorio.

Drafting of the article: J. Douketis, M. Marcucci, T. Baglin, S. Eichinger.

Critical revision of the article for important intellectual content: J. Douketis, A. Tosetto, M. Marcucci, T. Baglin, M. Cushman, S. Eichinger, D. Poli, R.C. Tait, A. Iorio.

Final approval of the article: J. Douketis, A. Tosetto, M. Marcucci, T. Baglin, M. Cushman, S. Eichinger, G. Palareti, D. Poli, R.C. Tait, A. Iorio.

Provision of study materials or patients: M. Cushman, S. Eichinger, G. Palareti, D. Poli, R.C. Tait.

Statistical expertise: M. Marcucci, A. Iorio.

Administrative, technical, or logistic support: J. Douketis, M. Cushman, S. Eichinger.

Collection and assembly of data: J. Douketis, M. Marcucci, T. Baglin, M. Cushman, S. Eichinger, R.C. Tait, A. Iorio.


Ann Intern Med. 2010;153(8):523-531. doi:10.7326/0003-4819-153-8-201010190-00009
Text Size: A A A

This article has been corrected. For original version, click "Original Version (PDF)" in column 2.

Background: In patients with a first unprovoked venous thromboembolism (VTE), an elevated d-dimer level after anticoagulation is stopped is a risk factor for recurrent VTE. However, questions remain about the utility of measuring d-dimer in clinical practice.

Purpose: To determine whether the timing of testing, patient age, and the cut point used to define a positive or negative result affect the ability of d-dimer testing to distinguish risk for recurrent disease.

Data Sources: Comprehensive search of electronic databases (MEDLINE, EMBASE, CINAHL, and the Cochrane Central Register of Controlled Trials) until July 2010, supplemented by reviewing conference abstracts and contacting content experts.

Study Selection: 7 prospective studies that investigated an association between d-dimer, measured after stopping anticoagulation, and disease recurrence in patients with a first unprovoked VTE (proximal deep venous thrombosis, pulmonary embolism, or both).

Data Extraction: Patient-level databases were obtained, transferred to a central database, checked, completed with further information provided by study investigators, and pooled into a single database.

Data Synthesis: 1818 patients with a first unprovoked VTE were followed for a mean of 26.9 months (SD, 19.1). A study-stratified multivariate Cox regression model, which included patient age, sex, hormone therapy use at the time of the index event, body mass index, timing of postanticoagulation d-dimer testing, and inherited thrombophilia as possible confounders, indicated that the hazard ratio for d-dimer status (positive vs. negative) was 2.59 (95% CI, 1.90 to 3.52). Only male sex had a significant effect on risk for recurrent VTE independent of d-dimer status. The Cox regression model and the log-rank test confirmed that the risk for recurrent VTE was higher in patients with a positive d-dimer result than in those with a negative result, regardless of the timing of postanticoagulation d-dimer testing or patient age. No study- or assay-specific d-dimer effect was found, and reassessing the analysis after recoding data according to specific quantitative d-dimer cut points (500 µg/L and 250 µg/L) did not change the results.

Limitations: Unmeasured variables could have affected the risk for recurrent VTE. The study population was predominantly white.

Conclusion: In patients with a first unprovoked VTE who have their d-dimer level measured after stopping anticoagulation, the timing of d-dimer testing, patient age, and the assay cut point used do not affect the ability of d-dimer to distinguish patients with a higher or lower risk for recurrent VTE.

Primary Funding Source: None.

Figures

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Appendix Figure 1.
Summary of evidence search and selection.

VTE = venous thromboembolism.

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Appendix Figure 2.
Derivation of patient population from source studies.

VTE = venous thromboembolism.

* References (1622).

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Appendix Figure 3.
Cox-derived cumulative hazard for recurrent VTE, by d-dimer status and patient sex (regardless of previous hormone-associated VTE).

HT = hormone therapy; VTE = venous thromboembolism.

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Figure 1.
Cox-derived cumulative hazard for recurrent venous thromboembolism, by d-dimer status in patient subgroups defined by timing of d-dimer testing after anticoagulation.
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Figure 2.
Cox-derived cumulative hazard for recurrent venous thromboembolism, by d-dimer status in patient subgroups defined by age.
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Appendix Figure 4.
Cox-derived cumulative hazard for recurrent venous thromboembolism, by d-dimer status as defined by 500- and 250-µg/L cut points.
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Appendix Figure 5.
Cox-derived cumulative hazard for recurrent venous thromboembolism, at 3-year follow-up, by quantitative d-dimer values.

Curve truncated at 2000 µg/L.

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Estrogen Associated VTE and Gender
Posted on November 4, 2010
Marc A. Rodger
Ottawa Hospital
Conflict of Interest: None Declared

Dear Editor,

Douketis et al are to be congratulated for an excellent collaborative project that yields useful insights in the important area of defining who is at high risk of recurrent venous thromboembolism (VTE)(1).

Confounding between age, estrogen associated VTE and gender are an important challenge in analysis of their data given: 1) the weak association between estrogen exposure (from pregnancy, oral contraceptives (OC) and hormone replacement)and VTE(2); 2) the fact that the estrogen exposure does not occur in men and rarely in older women; and 3)the apparent association between older age and recurrent VTE in women(3). A robust analysis could have answered the important question of whether the lower risk of recurrent VTE in a young woman on OC is due to her age, gender, the subsequent removal of the "provoking" factor (i.e. OC) or some combination of these. Given the low absolute risk of first VTE with estrogen exposure(2) it is unlikely the removal of the OC alone can account for the low risk of recurrent VTE in this population.

The authors chose to classify gender in 3 categories: men, women with estrogen associated VTE and women without estrogen associated VTE to attempt to deal with estrogen and gender confounding. However, this stratification does not permit assessment of confounding by age. We would suggest that a more informative analysis would stratify gender into male and female subgroups and then include estrogen exposure and age as covariates in the female sub-group and age in the male sub-group.

Finally, this re-analysis would be clinically important as it would allow the authors to determine whether D-Dimer, BMI> 30 and age over 65 are risk factors for recurrent VTE in the female and the male subgroups. In our analysis(3), these were among the most important risk factors for recurrent VTE in women but were not at all significant in men.

Marc A. Rodger, MD, MSc Timothy Ramsay, PhD Gregoire Le Gal, MD, PhD Marc Carrier, MD, MSc

Ottawa Hospital Ottawa, Ontario K1H 8L6 Canada

References

1. Douketis J, Tosetto A, Marcucci M, Baglin T, Cushman M, Eichinger S et al. Patient-level meta-analysis: effect of measurement timing, threshold, and patient age on ability of D-dimer testing to assess recurrence risk after unprovoked venous thromboembolism. Ann Intern Med 2010;153(8):523-31.

2. Renoux C, Dell'Aniello S, Suissa S. Hormone replacement therapy and the risk of venous thromboembolism: a population-based study. J Thromb Haemost 2010;8(5):979-86.

3. Rodger MA, Kahn SR, Wells PS, Anderson DA, Chagnon I, Le Gal G et al. Identifying unprovoked thromboembolism patients at low risk for recurrence who can discontinue anticoagulant therapy. CMAJ 2008;179:417- 26.

Conflict of Interest:

None declared

Is the ability of D-dimer to predict VTE recurrence sex and age specific?
Posted on November 5, 2010
Valerie Olie
Inserm, CESP, U1018, Hormones and Cardiovascular diseases Team
Conflict of Interest: None Declared

Dear Editor,

In a meta-analysis of seven studies, Dr Douketis and colleagues report that the timing of D-dimer testing and patient age do not affect the ability of D-dimer to distinguish risk of recurrent venous thromboembolism. These findings could influence the duration of secondary prophylaxis against venous thromboembolism recurrence, and are of first importance considering that the case fatality rate after discontinuing anticoagulant can reach 9% (1). However, the risk of recurrent VTE have to be counterbalanced by the risk of major hemorrhage, an important drawback of vitamin K antagonist, especially among old patients. In an ongoing prospective and multicenter cohort study using a similar design (2), 583 patients (234 men and 349 women) with unprovoked first venous thromboembolism were followed-up for an average of 27 months after anticoagulation was stopped. Recurrence occurred in 36 men and 38 women. D -dimer were measured in average 12 weeks after anticoagulation was stopped with a ELISA assay which used a cut point of 500 microg/L. Using a Cox proportional hazard model we found that elevated D-dimer were a risk factor for recurrent VTE in women but not in men (hazard ratio, 2.59 (95% Confidence Interval, 1.20-5.60); 0.8 (95% CI; 0.5-1.4) respectively, p for interaction=0.01). In addition, D-dimer status (positive vs. negative) was associated with an increased risk of recurrent VTE in women younger than 65 but not in women older than 65 years (hazard ratio, 3.55 (95% Confidence Interval, 1.31-9.60); 0.67 (95% CI; 0.21-2.19) respectively, p for interaction=0.01). Modification of the D-dimer cut point among women older than 65 years did not change the results. While the discrepancy between men and women regarding the ability of D-dimer status to distinguish recurrent risk have been previously described (3), the lack of association between D-dimer status and recurrent among women older than 65 years can be partly explained by the decrease of the predictive value of most of risk factors with age (4, 5). Considering our result and the increased risk of bleeding among elderly population, D-dimer status in older patients should be interpreted with caution and may not be considered sufficient to indicate prolong anticoagulation. Further data are needed to assess an individual benefits/risk profile for indefinite anticoagulation especially among elderly.

References

1. Douketis JD, Gu CS, Schulman S, Ghirarduzzi A, Pengo V, Prandoni P. The risk for fatal pulmonary embolism after discontinuing anticoagulant therapy for venous thromboembolism. Ann Intern Med. 2007;147(11):766-74. 2. Oli? V, Zhu T, Martinez I, Scarabin PY, Emmerich J. Sex-specific risk factors for recurrent venous thromboembolism. Arterioscler Thromb Vasc Biol. . 2010;30:e183-e321. 3. Rodger MA, Kahn SR, Wells PS, et al. Identifying unprovoked thromboembolism patients at low risk for recurrence who can discontinue anticoagulant therapy. Cmaj. 2008;179(5):417-26. 4. Schutgens RE, Haas FJ, Biesma DH. Reduced efficacy of clinical probability score and D-dimer assay in elderly subjects suspected of having deep vein thrombosis. Br J Haematol. 2005;129(5):653-7. 5. Carcaillon L, Gaussem P, Ducimetiere P, et al. Elevated plasma fibrin D -dimer as a risk factor for vascular dementia: the Three-City cohort study. J Thromb Haemost. 2009;7(12):1972-8.

Conflict of Interest:

None declared

Author's Reply
Posted on December 20, 2010
James D. Douketis
Department of Medicine and Dept of Clinical Epidemiology and Biostatistics, McMaster University, ON
Conflict of Interest: None Declared

We agree with Dr. Rodger and associates that in patients with venous thromboembolism (VTE) teasing out the effects of patient age, sex, and hormonal therapy (oral contraceptives, estrogen replacement) is important to estimate an individual patient's risk for disease recurrence and, in turn, their need for long-term anticoagulation. Although recurrent VTE appears higher in men than women [1,2], as Dr. Rodger rightly points out, the assessment of the effect of patient sex might be confounded by age and hormonal therapy (women receiving oral contraceptives, typically, are younger and stop hormonal therapy after VTE). We also acknowledge that we could have better articulated our rationale for classifying patient groups according to sex and hormonal exposure prior to VTE and how potential confounders were handled.

However, we respectfully disagree that the patient classification we used for analysis purposes precludes an assessment of confounding by age, which we obtained in the Cox regression analyses by including interaction terms between age and candidate covariates. We assessed all bivariate interactions in our final model (including age, body mass index, and D- dimer) for any effect on our main estimates of interest (relating to the predictive utility of post-anticoagulation D-dimer) and subsequently withdrew all of them, due to absence of effect, to spare degrees of freedom. Our estimate of the predictive effect of D-dimer is, we believe, adequately adjusted for age, sex and any possible interactions. Although our study focused on assessing the value of post-anticoagulation D-dimer to distinguish risk for recurrence after VTE, we plan to address the issue of risk differential of recurrence in men and women separately.

In the study by Rodger and associates [2], elevated D-dimer during anticoagulant therapy, obesity, and age >65 years were predictors of recurrent VTE in women. In our analysis, we did not find patient sex, age and obesity affected the predictive utility of D-dimer but it is likely that these factors will be useful in a clinical prediction guide to distinguish risk for recurrence among patients with VTE, especially those who have no antecedent risks or 'mild antecedent risks' such as hormonal therapy. We look forward to findings from planned studies by Rodger and associates [4], and other investigators [5-7] to better inform clinical practice.

References

1. McRae S, Tran H, Schulman S, Ginsberg J, Kearon C. Effect of patient's sex on risk of recurrent venous thromboembolism: a meta- analysis. Lancet. 2006;368:371-378. 2. Rodger MA, Kahn SR, Wells PS, Anderson DA, Chagnon I, Le Gal G, et al. Identifying unprovoked thromboembolism patients at low risk for recurrence who can discontinue anticoagulant therapy. CMAJ. 2008;179:417- 26. 3. Douketis J, Tosetto A, Marcucci M, Baglin T, Cushman M, Eichinger S et al. Patient-level meta-analysis: effect of measurement timing, threshold, and patient age on ability of D-dimer testing to assess recurrence risk after unprovoked venous thromboembolism. Ann Intern Med. 2010;153:523-531.

4. Clinical Decision Rule Validation Study to Predict Low Recurrent Risk in Patients with Unprovoked Venous Thromboembolism (REVERSEII). clinicaltrials.gov/ct2/show/NCT00967304.

5. D-dimer to Select Patients with a First Unprovoked Venous Thromboembolism who Can have Anticoagulants Stopped at 3 Months (DODS). clinicaltrials.gov/ct2/show/NCT00720915.

6. D-dimer and Ultrasonography in Combination Italian Study (DULCIS). clinicaltrials.gov/ct2/show/NCT00954395.

7. VISTA Trial, personal communication (Karel Moons, May 2010).

Conflict of Interest:

None declared

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