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Role of an age-adjusted D-dimer cutoff level in the diagnosis algorithm of lower limb deep venous thrombosis in outpatients
Role of an age-adjusted D-dimer cutoff level in the diagnosis algorithm of lower limb deep venous thrombosis in outpatients Xavier Jimenez-Guiu, MD, Antonio Romera-Villegas, MD, PhD, Malka Huici-Sanchez, MD, Carlos Martinez-Rico, MD, and Ramon Vila-Coll, MD, Hospitalet del Llobregat, Spain
ABSTRACT Objective: Our goal was to analyze the utility of the age-adjusted D-dimer cutoff value in patients with clinically suspected deep venous thrombosis (DVT) in an ambulatory care setting, including distal DVTs. Methods: This was an observational cohort study of 606 outpatients older than 18 years presenting with low or moderate clinical suspicion of lower limb DVT (measured by Wells scale). D-dimer levels were obtained, and duplex ultrasound was performed (including femoropopliteal and below-knee veins). We calculated sensitivity, specificity, and positive and negative predictive D-dimer values and when to apply the age-adjusted D-dimer cutoff value (D-dimer threshold ¼ age 10 mg/L). We split patients older than 50 years into 10-year age groups. We constructed receiver operating characteristic curves of the D-dimer test for each group to find the best threshold (defined as the value of D-dimer that gives more specificity, maintaining the maximum possible sensitivity). Results: There were 249 men and 357 women with a mean age of 69.3 years; 41 patients were diagnosed with DVT. At a D-dimer threshold of 250 mg/L, sensitivity was 93%, specificity was 8%, positive predictive value was 7%, and negative predictive value was 94%. When the age-adjusted cutoff level was applied, global sensitivity was 76% and specificity 61%; positive predictive value was 12%, and negative predictive value was 97%. False-negative rate was 24%. We split patients older than 50 years into 10-year age groups: 50 to 60 years, 60 to 70 years, 70 to 80 years, and >80 years. The optimum thresholds were, respectively, 526 mg/L, 442.5 mg/L, 475 mg/L, and 549. mg/L. Conclusions: In our series, the age-adjusted D-dimer cutoff level is not useful in the diagnostic algorithm of DVT. (J Vasc Surg: Venous and Lym Dis 2019;-:1-7.) Keywords: Deep venous thrombosis; Age-adjusted D-dimer cutoff level; Distal deep venous thrombosis; Calf deep venous thrombosis; Age-adjusted threshold
Thromboembolic venous disease includes two clinical entities, pulmonary embolism and deep venous thrombosis (DVT), and has an incidence rate of 104 to 183 per 100,000 population/year.1 The diagnosis of these patients in emergency care is based on an algorithm that includes the use of clinical probability scales, D-dimer levels, and compression ultrasound (CUS).2 When clinical probability is high, despite D-dimer levels, it is mandatory to perform a CUS examination to confirm or to discard the presence of a DVT.2 On the other hand, when the pre-test clinical probability (PTCP) is low or moderate, the diagnosis of DVT can be safely excluded with a normal D-dimer blood level, avoiding the need for CUS.2
From the Angiology and Vascular Surgery Unit, Bellvitge University Hospital. Author conflict of interest: none. Correspondence: Xavier Jimenez-Guiu, MD, Angiology and Vascular Surgery Unit, Bellvitge University Hospital, C/Feixa Llarga s/n, 08907 Hospitalet del Llobregat, Spain (e-mail: [email protected]). The editors and reviewers of this article have no relevant financial relationships to disclose per the Journal policy that requires reviewers to decline review of any manuscript for which they may have a conflict of interest. 2213-333X Copyright Ó 2019 by the Society for Vascular Surgery. Published by Elsevier Inc. https://doi.org/10.1016/j.jvsv.2019.11.015
Improvements in the diagnosis and treatment of DVTs during the last decades have enabled affected patients to be completely managed as outpatients, except for some particular cases.3 Despite these advancements, which clearly provide better and more convenient care for the patients, the emergency staff may be overwhelmed by the huge number of CUS examinations, which are sometimes unnecessary. To improve the accuracy of D-dimer as a marker of DVT, it has been proposed that cutoff values be adjusted by age.4-8 Most studies made these adjustments on the basis of a limited CUS examination that included only the femoropopliteal segment and not the infrapopliteal veins.5-8 None of the available evidence concerning age-adjusted D-dimer thresholds included examination of distal veins in the CUS examination protocol, and this might have biased their results. It is well known that acute lower limb DVTs may start anywhere in the venous system. They usually start in the calf veins and extend proximally. The diagnosis and management of these isolated distal DVTs (IDDVTs) are still under discussion,9 as is the role of D-dimer in the diagnostic algorithm. In 2014, a prospective study published by Sartori et al10 showed a false-negative rate of 14.4% for D-dimer in patients with acute IDDVT, although the timing between symptoms and the diagnosis was not 1
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reported and there was no clear differentiation between cases of acute DVT and chronic DVT. The need for treatment is uncertain with IDDVT; it should be considered because IDDVT has a potential risk (up to 15.5%) of proximal progression9,11 and a recurrence rate up to 18%,12 and pulmonary embolism (symptomatic and asymptomatic) is caused by IDDVT in up to 50% of patients.13-15 Present clinical guidelines recommend treating IDDVT with anticoagulation when it is symptomatic or has any of the following characteristics: the D-dimer level is abnormal; the thrombosis is extensive (>5 cm in length, involving multiple veins, or >7 mm in diameter); the patient has active cancer; there is a history of venous thromboembolism; the thrombosis is close to the proximal veins; or the provoking factor is not reversible.11 The goal of this study was to analyze the utility of age-adjusted D-dimer cutoff values in patients with clinically suspected DVT, including IDDVT, in an ambulatory setting.
METHODS We performed a prospective observational cohort study of 606 consecutive outpatients older than 18 years presenting to the emergency department between January and December 2016 with clinically suspected acute lower limb DVT (suspected by a family physician or emergency physician). Exclusion criteria were patients whose clinical onset occurred >15 days before (not acute DVT), refusal or inability of the patient to consent to the study, and patients currently being treated with anticoagulation. All patients were clinically assessed by a vascular surgeon, and the PTCP score was calculated (following Wells criteria16). We used the categorical variable of low, medium, or high PTCP because it is more accurate than the likely/unlikely classification and more useful because patients with a score of 2 can be classified as patients in whom D-dimer testing may be helpful, not requiring more diagnostic tools, whereas these patients require CUS when the two-level Wells rule is used. In all patients, we obtained D-dimer levels by turbidimetry technique with ACL TOP 550 (reagent D-Dimer HS; Instrumentation Laboratory, Bedford, Mass) with a Ddimer standard cutoff of 250 mg/L D-dimer units, which would be comparable to 500 mg/L fibrinogenequivalent units.17 We performed a complete CUS examination including femoral, popliteal, calf, peroneal, and tibial veins after the clinical evaluation and D-dimer test result. Lower limb venous CUS examination was performed by medical physicians of the Angiology and Vascular Surgery Unit using Philips Epiq 5 equipment (Philips Healthcare N.V., Best, The Netherlands) with a 510 MHz transducer for the infrainguinal area and a 3.5 MHz transducer for insonation of abdominal vessels. The examination was performed in a supine position for the femoropopliteal sector and in the standing or reverse Trendelenburg position for the distal area. The
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ARTICLE HIGHLIGHTS d
d
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Type of Research: Single-center prospective nonrandomized cohort study Key Findings: In patients with isolated distal deep venous thrombosis (DVT), a comparison was conducted of results of the common D-dimer threshold in 606 patients with low or moderate clinical suspicion of lower limb DVT (by Wells criteria) and the age-adjusted D-dimer threshold (D-dimer threshold ¼ age 10 mg/L). The sensitivity decreased from 93% to 76%, proving not to be a useful screening test. Take Home Message: The authors suggest that the age-adjusted D-dimer threshold is not useful in the diagnostic algorithm for DVT when distal veins are routinely scanned.
deep veins were examined using compression by the transducer on B mode in the cross-sectional view. Color flow was used to detect luminal filling defects, and Doppler tracings were also obtained to detect spontaneous flow and phasicity. The diagnosis was established using the following ultrasound criteria: no collapse or partial collapse of the vein lumen at transducer compression; thrombus visualization within the vein lumen; absence of spontaneous venous flow; absence of Doppler signal; and increase in vein diameter. At least two of these criteria had to be present for diagnosis of DVT. We looked for a new threshold of D-dimer using the same strategy as Douma et al18 to adjust the D-dimer level according to age in the algorithm to rule out pulmonary embolism. For this purpose, we divided patients older than 50 years into 10-year age groups. We constructed receiver operating characteristic (ROC) curves of the D-dimer test for each group to find the best threshold (defined as the value of D-dimer that gives more specificity while maintaining the maximum possible sensitivity). We considered oncologic patients as a possible confounding factor, so we performed the same analysis with nononcologic patients. Categorical variables were presented as the number of cases and percentages; continuous variables were presented as the mean and standard deviation or median and interquartile range. To assess possible relationships, we plotted the proportion of DVTs for each quantile of age. To assess the accuracy of the D-dimer cutoff value of 250 mg/L, we computed the sensitivity, specificity, and positive and negative predictive values. The same procedure was done to evaluate the age-adjusted Ddimer cutoff value (10 mg/L).19 Finally, to avoid population bias, we performed the first analysis without including IDDVTs to see whether our population results were similar to those reported in the literature.
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Fig 1. Flow diagram of the study. Of 836 patients with clinically suspected lower limb deep venous thrombosis (DVT), 205 had a high pre-test clinical probability (PTCP) of DVT and were excluded. Of the 631 left, 606 met the inclusion criteria. Of those patients, 565 did not had DVT and 41 did.
Because of the exploratory nature of the study in the analysis of the utility of age-adjusted D-dimer cutoff values in patients with clinically suspected DVT, sample size estimation was performed strictly on the basis of the maximum marginal error of estimate sensitivity. Values of sensitivity of age-adjusted D-dimer cutoff values and prevalence of DVT were hypothesized as 85% and 10%, respectively. In order for the maximum marginal error of estimate sensitivity not to exceed 7% with a 95% confidence level, the total required sample size was 600. A dropout rate of 15% was assumed.
The project was approved by the Investigation Ethics Committee of Hospital Universitari de Bellvitge (Reference PR421/17). The study was performed following the Helsinki Declaration consensus (Fortaleza, 2013). All data from patients were treated according to General Data Protection Regulation rules and Spanish laws LOPD 15/1999 and RD 1720/2007. All data were codified using a numeric code anonymously established for the purpose of this study. The investigation data were saved in an electronic directory with restricted access supervised by the Information Systems of Hospital Universitari de Bellvitge. Analyses were performed with R software 3.4.0.20
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Fig 2. Box plots showing patients with and without deep venous thrombosis (DVT) according to D-dimer levels and pre-test clinical probability (PTCP).
RESULTS Our study population included 249 men (41.1%) and 357 women (58.9%) with a mean age of 69.3 years, and 92 of these patients had an active neoplasm (15.2%). The Wells PTCP was moderate in 142 patients (23.4%) and low in 464 patients (76.6%; Fig 1). The D-dimer level of patients with low or moderate clinical probability of DVT was heterogeneous (Fig 2). Forty-one patients were diagnosed with DVT; the prevalence of DVT in the study group was 6.7%, and the proportion of DVT for each age group was homogeneous (Fig 3). The overall prevalence in our population (including high PTCP) was 26.8%. The most common area affected was distal (53.7%), followed by popliteal (29.3%), femoropopliteal (9.76%), and femoral (4.8%). One patient had an iliac DVT. Of the patients who had a DVT, 2.5% were in the low PTCP group and 20% were in the moderate PTCP group. At the threshold of 250 mg/L, global sensitivity was 93% (95% confidence interval [CI], 0.8-0.98) with a specificity of 8% (95% CI, 0.06-0.11), positive predictive value of 7% (95% CI, 0.05-0.09), and negative predictive value of 94% (95% CI, 0.83-0.99). Three patients had a D-dimer level below 250 mg/L but were diagnosed with DVT by CUS; one was femoral and two were distal. When the age-adjusted cutoff level was applied, global sensitivity was 76% (95% CI, 0.60-0.88), specificity was 61% (95% CI, 0.57-0.65), positive predictive value was 12% (95%
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CI, 0.09-0.17), and negative predictive value was 97% (95% CI, 0.95-0.99). The false-negative rate was 24%. Ten patients had a normal age-adjusted D-dimer cutoff level but were diagnosed with DVT by ultrasound. Of these 10 patients, 8 had a distal DVT and 2 had a proximal DVT. We separated patients older than 50 years into four 10-year age groups: 50 to 60 years, 60 to 70 years, 70 to 80 years, and >80 years. The optimum thresholds were 526 mg/L (sensitivity 100%, specificity 51%), 442.5 mg/L (sensitivity 100%, specificity 43%), 475 mg/L (sensitivity 81%, specificity 31%), and 549 mg/L (sensitivity 100%, specificity 55%), respectively (Fig 4; ROC curves for all patients are shown in Fig 5, A). We then performed the same analysis without cancer patients. Our nononcologic study population included a total of 514 patients. Of them, 405 patients (78.8%) had a low PTCP and 109 (21.2%) had a moderate PTCP. The prevalence of lower limb DVT was 6% (31 cases). The sectors affected were the distal sector (51.8%), followed by the popliteal (29%), femoral (6.4%), and finally the femoropopliteal and iliofemoral (3.2% each). The sensitivity of D-dimer with a classic threshold of 250 mg/L was 90% (95% CI, 0.74-0,98), with a specificity of 7% (95% CI, 0.05-0.10). The negative predictive value was 92% (95% CI, 0.79-0.98). Three patients were diagnosed with DVT by CUS but had a normal D-dimer level. When we applied the age-adjusted D-dimer cutoff level, the sensitivity was 74% (95% CI, 0.55-0.88) and the specificity was 61% (95% CI, 0.56-0.65). The negative predictive value was 97% (95% CI, 0.95-0.99), and the false-negative rate was 26%. Eight patients were diagnosed with DVT by CUS but had a normal age-adjusted D-dimer level; six DVTs were distal and two were proximal. After splitting patients older than 50 years in 10-year age groups, we obtained four groups: 50 to 60 years, 60 to 70 years, 70 to 80 years, and >80 years. The optimum thresholds were 523 mg/L (sensitivity 100%, specificity 48%), 442 mg/L (sensitivity 100%, specificity 44%), 641 mg/ L (sensitivity 71%, specificity 52%), and 763 mg/L (sensitivity 100%, specificity 71%), respectively (Fig 4; ROC curves for all patients are shown in Fig 5, B). We could not perform a linear regression (in all patients and in nononcologic patients) because the curve was a parabola and there was not a correlating regression line. On excluding IDDVTs and applying the age-adjusted D-dimer threshold, sensitivity was 89% (95% CI, 0.67-0.99) with a specificity of 61% (95% CI, 0.57-0.65), positive predictive value of 7% (95% CI, 0.04-0.11), and negative predictive value of 99% (95% CI, 0.98-1.00).
DISCUSSION
Fig 3. Distribution of deep venous thromboses (DVTs) among quantiles of age.
In this study, we found a lower sensitivity for the ageadjusted D-dimer cutoff level than with the normal threshold in patients with clinically suspected lower limb DVT when the calf and distal areas were included in the CUS examination. Treatment of IDDVT is still being debated, and clinical guidelines recommend treatment
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Fig 4. Optimum threshold for D-dimer level per age group (maintaining maximum sensitivity and highest possible specificity) in global population and in nononcologic patients. A similar analysis was performed by Douma et al18 to obtain the age-adjusted D-dimer level formula for pulmonary embolism. In our results, we can see that the progression of the best D-dimer threshold does not increase according to age. Moreover, it decreases in the 60- to 70-year and 70- to 80-year age groups compared with the 50- to 60-year age group.
with anticoagulation when patients are symptomatic or when extensive risk factors are present (grade 2C).11 Otherwise, a second CUS examination should be performed in 2 weeks (grade 2C) to see whether there has been proximal progression, following Chest Guidelines
2016 recommendations.11 These recommendations emphasize that there is not a consensus on IDDVT treatment. This is due to a lack of studies, especially randomized clinical trials, as all available studies are systematic reviews.21,22 Despite this, our multidisciplinary DVT team
Fig 5. Receiver operating characteristic (ROC) curves of the D-dimer test for each 10-year age group (A) and ROC curves of the D-dimer test for each 10-year age group without oncologic patients (B). In A, we represent ROC curves for each 10-year age group including all patients of the study. From those ROC curves, we obtained the optimum threshold for the D-dimer level of every age group to find a directly proportional relationship between D-dimer and age. The same happened when we excluded oncologic patients (to avoid a potential bias).
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always extends the CUS examination to distal veins to check for IDDVT, given their risk of recurrence (up to 18%)9,11 and progression (up to 15%),12 and because it is sometimes the first sign of an underlying disease. When we analyzed the inclusion and exclusion criteria in the published studies, the peroneal, tibial, and calf veins were not included in the CUS examinations. In 2010, Douma et al5 studied the results obtained in five different cohorts of patients. In one cohort, the CUS examination included the trifurcation of calf veins, but no veins below the knee veins were explored; in fact, the sectors affected were not described in the results of any of the cohorts. The same happened in the studies by Cini et al,7 Hamblin et al,6 and Takach Lapner et al,23 in which only the proximal areas were studied. In 2018, Gómez-Jabalera et al24 published a study similar to previous reports but looking for other possible thresholds (multiplying the age 10, 15, 20, 25, and 30 mg/L). The CUS protocol included calf veins but not peroneal or tibial veins. The sectors affected were not included in the results. Our results differ from those published in the reference studies,5-8,23-27 in which the false-negative rates were between 0% and 4.8% when the age-adjusted D-dimer level was applied. We had a 24% false-negative rate, which is surprisingly high compared with the 7% falsenegative rate for the classic cutoff level. We performed the analysis excluding IDDVTs to see whether our population differed from the reference studies, but results were similar to those published before. Our data suggest that the age-adjusted D-dimer cutoff value is not worthwhile when distal veins are scanned. The prevalence of DVT depends on the study population and the inclusion and exclusion criteria used in selection of patients. In published literature, the prevalence of DVT in the low-intermediate PTCP group (when Wells 1997 classification was applied) ranges from 4.2% to 51.6%. This indicates the heterogeneity of the studies. In our population, 2.5% of patients in the low PTCP group and 20% of patients in the moderate PTCP group were diagnosed with DVT. These prevalence values are similar to what Wells found in 1997 (prevalence of 3% for the low PTCP group and 16% for the moderate PTCP group). There are discrepancies in terms of reference ranges and clinical thresholds for the exclusion of thrombosis because there are many possible combinations between monoclonal antibodies and different assay reagents. In the reported studies, there is a wide difference in the tests used. Some authors used enzyme-linked immunosorbent assay (for example, with VIDAS [bioMérieux, Marcy-l’Étoile, France]5); others used second-generation latex agglutination techniques (like STA-Liatest [Diagnostica Stago, Asnières sur Seine, France]6); and in other studies, the D-dimer determination was made using a mix of different assays.5,27 Moreover, most of the time,
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these different laboratory tests are not validated prospectively on each population to determine the optimum threshold. Because of this heterogeneity of laboratory methods, we think that it is not proper to use the age-adjusted D-dimer threshold indiscriminately before validating your laboratory results and study population. Our study has been developed in a tertiary hospital that is the reference for an area of secondary and primary hospitals that have D-dimer as a tool before referring patients to us. That is why our population had mostly an abnormal D-dimer level. Despite having seven more false-negative results, there was an improvement of the negative predictive value from 94% to 97%. This is because the number of true negatives rose from 45 to 336 patients when the age-adjusted formula was applied. Even with negative predictive value outcomes, we think that leaving 10 patients undiagnosed is inadmissible because of the potential morbidity and mortality of DVTs. We performed an analysis similar to that of Douma et al18 to find the optimum number by which to multiply age to obtain a threshold with the maximum specificity without losing sensitivity. We found that the thresholds measured by ROC curves in 10-year age groups (in patients older than 50 years) were different from the ones found for pulmonary embolism. We did not find an ascending curve; in contrast, the optimal threshold rises from 525.6 mg/L in patients between 50 and 60 years old to 549.5 mg/L in patients older than 80 years and has a parabolic curve. We performed the same analysis in nononcologic patients and found similar results. These results call into question the relationship between the age-adjusted D-dimer level and DVT in patients with low and moderate PTCP. It also signifies the importance of validating our own D-dimer assays and reagents to obtain the optimum threshold for every reference population and of judging the requirement and utility of an age-adjusted threshold application. The main limitation of the study was that a quarter of patients arrived from smaller hospitals. Therefore, there could be a number of undiagnosed DVTs with use of clinical criteria different from ours. The small size of our sample also reflects the difficulty of studying this group of patients, in which the prevalence of DVT is low.
CONCLUSIONS The age-adjusted D-dimer cutoff level did not show linear progression among age groups in our series. Therefore, it is not useful in the diagnostic algorithm for DVT when distal veins are routinely scanned. We would like to thank Statistics Advisory Service at IDIBELL collaboration for their help with our analyses.
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AUTHOR CONTRIBUTIONS Conception and design: XJG, ARV, RVC Analysis and interpretation: XJG, ARV, MHS, CMR, RVC Data collection: XJG, ARV, MHS Writing the article: XJG, ARV, MHS Critical revision of the article: XJG, ARV, MHS, CMR, RVC Final approval of the article: XJG, ARV, MHS, CMR, RVC Statistical analysis: XJG, ARV Obtained funding: Not applicable Overall responsibility: XJG
REFERENCES 1. Heit JA. Epidemiology of venous thromboembolism. Nat Rev Cardiol 2015;12:464-74. 2. Wells PS, Anderson DR, Rodger M, Forgie M, Kearon C, Dreyer J, et al. Evaluation of D-dimer in the diagnosis of suspected deep-vein thrombosis. N Engl J Med 2003;349: 1227-35. 3. Condliffe R. Pathways for outpatient management of venous thromboembolism in a UK centre. Thromb J 2016;14:1-8. 4. Nybo M, Hvas AM. Age-adjusted D-dimer cut-off in the diagnostic strategy for deep vein thrombosis: a systematic review. Scand J Clin Lab Invest 2017;77:568-73. 5. Douma RA, Tan M, Schutgens RE, Bates SM, Perrier A, Legnani C, et al. Using an age-dependent D-dimer cut-off value increases the number of older patients in whom deep vein thrombosis can be safely excluded. Haematologica 2012;97:1507-13. 6. Hamblin AD, Cairns K, Keeling DM. The use of agedependent D-dimer cut-off values to exclude deep vein thrombosis. Haematologica 2012;97:43-4. 7. Cini M, Legnani C, Frascaro M, Sartori M, Cosmi B, Palareti G. D-dimer use for deep venous thrombosis exclusion in elderly patients: a comparative analysis of three different approaches to establish cut-off values for an assay with results expressed in D-dimer units. Int J Lab Hematol 2014;36:541-7. 8. Broen K, Scholtes B, Vossen R. Predicting the need for further thrombosis diagnostics in suspected DVT is increased by using age adjusted D-dimer values. Thromb Res 2016;145:107-8. 9. Palareti G, Schellong S. Isolated distal deep vein thrombosis: what we know and what we are doing. J Thromb Haemost 2011;10:11-9. 10. Sartori M, Migliaccio L, Favaretto E, Palareti G, Cosmi B. Two years outcome of isolated distal deep vein thrombosis. Thromb Res 2014;134:36-40. 11. Kearon C, Akl EA, Ornelas J, Blaivas A, Jimenez D, Bounameaux H, et al. Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report. Chest 2016;149:315-52. 12. Gillet JL, Perrin MR, Allaert FA. Short-term and mid-term outcome of isolated symptomatic muscular calf vein thrombosis. J Vasc Surg 2007;46:513-20. 13. Guias B, Simoni G, Oger E, Lemire A, Leroyer C, Mottier D, et al. Thrombose veineuse musculaire du mollet et embolie pulmonaire. J Mal Vasc 1999;24:132-4.
14. Hollerweger A, Macheiner P, Rettenbacher T, Gritzmann N. Sonographic diagnosis of thrombosis of the calf muscle veins and the risk of pulmonary embolism. Ultraschall Med 2000;21:66-72. 15. Ohgi S, Tachibana M, Ikebuchi M, Kanaoka Y, Maeda T, Mori T. Pulmonary embolism in patients with isolated soleal vein thrombosis. Angiology 1998;49:759-64. 16. Wells PS, Anderson DR, Bormanis J, Guy F, Mitchell M, Gray L. Value of assessment of pretest probability of deepvein thrombosis in clinical management. Lancet 1997;350: 1795-8. 17. Keeling DM, Mackie IJ, Moody A, Watson HG; Haemostasis and Thrombosis Task Force of the British Committee for Standards in Haematology. The diagnosis of deep vein thrombosis in symptomatic outpatients and the potential for clinical assessment and D-dimer assays to reduce the need for diagnostic imaging. Br J Haematol 2004;124:15-25. 18. Douma RA, le Gal G, Söhne M, Righini M, Kamphuisen PW, Perrier A, et al. Potential of an age adjusted D-dimer cut-off value to improve the exclusion of pulmonary embolism in older patients: a retrospective analysis of three large cohorts. BMJ 2010;340:1475. 19. Zhou XA, Obuchowski NA, McClish DK. Statistical methods in diagnostic medicine. 2nd ed. Hoboken, NJ: Wiley; 2011. 20. R Core Team. R: a language and environment for statistical computing. Vienna, Austria: R Foundation for Statistical Computing; 2018. 21. Masuda EM, Kistner RL, Musikasinthorn C, Liquido F, Geling O, He Q. The controversy of managing calf vein thrombosis. J Vasc Surg 2012;55:550-61. 22. De Martino RR, Wallaert JB, Rossi AP, Zbehlik AJ, Suckow B, Walsh DB. A meta-analysis of anticoagulation for calf deep venous thrombosis. J Vasc Surg 2012;56:228-37. 23. Takach Lapner S, Julian JA, Linkins LA, Bates SM, Kearon C. Questioning the use of an age-adjusted D-dimer threshold to exclude venous thromboembolism: analysis of individual patient data from two diagnostic studies. J Thromb Haemost 2016;14:1953-9. 24. Gómez-Jabalera E, Bellmunt Montoya S, Fuentes-Camps E, Escudero Rodríguez J. Age-adjusted D-dimer for the diagnosis of deep vein thrombosis. Phlebology 2018;33:1-6. 25. Legnani C, Cini M, Scarvelis D, Toulon P, Wu JR, Palareti G. Multicenter evaluation of a new quantitative highly sensitive D-dimer assay, the Hemosil D-dimer HS 500, in patients with clinically suspected venous thromboembolism. Thromb Res 2010;125:398-401. 26. Bates SM, Kearon C, Crowther M, Linkins L, O’Donnell M, Douketis J, et al. A diagnostic strategy involving a quantitative latex D-dimer assay reliably excludes deep venous thrombosis. Ann Intern Med 2003;138:787-94. 27. Mullier F, Vanpee D, Jamart J, Dubuc E, Bailly N, Douxfils J, et al. Comparison of five D-dimer reagents and application of an age-adjusted cut-off for the diagnosis of venous thromboembolism in emergency department. Blood Coagul Fibrinolysis 2014;25:309-15.
Submitted Aug 2, 2019; accepted Nov 18, 2019.
ABSTRACT Objective: Our goal was to analyze the utility of the age-adjusted D-dimer cutoff value in patients with clinically suspected deep venous thrombosis (DVT) in an ambulatory care setting, including distal DVTs. Methods: This was an observational cohort study of 606 outpatients older than 18 years presenting with low or moderate clinical suspicion of lower limb DVT (measured by Wells scale). D-dimer levels were obtained, and duplex ultrasound was performed (including femoropopliteal and below-knee veins). We calculated sensitivity, specificity, and positive and negative predictive D-dimer values and when to apply the age-adjusted D-dimer cutoff value (D-dimer threshold ¼ age 10 mg/L). We split patients older than 50 years into 10-year age groups. We constructed receiver operating characteristic curves of the D-dimer test for each group to find the best threshold (defined as the value of D-dimer that gives more specificity, maintaining the maximum possible sensitivity). Results: There were 249 men and 357 women with a mean age of 69.3 years; 41 patients were diagnosed with DVT. At a D-dimer threshold of 250 mg/L, sensitivity was 93%, specificity was 8%, positive predictive value was 7%, and negative predictive value was 94%. When the age-adjusted cutoff level was applied, global sensitivity was 76% and specificity 61%; positive predictive value was 12%, and negative predictive value was 97%. False-negative rate was 24%. We split patients older than 50 years into 10-year age groups: 50 to 60 years, 60 to 70 years, 70 to 80 years, and >80 years. The optimum thresholds were, respectively, 526 mg/L, 442.5 mg/L, 475 mg/L, and 549. mg/L. Conclusions: In our series, the age-adjusted D-dimer cutoff level is not useful in the diagnostic algorithm of DVT. (J Vasc Surg: Venous and Lym Dis 2019;-:1-7.) Keywords: Deep venous thrombosis; Age-adjusted D-dimer cutoff level; Distal deep venous thrombosis; Calf deep venous thrombosis; Age-adjusted threshold
Thromboembolic venous disease includes two clinical entities, pulmonary embolism and deep venous thrombosis (DVT), and has an incidence rate of 104 to 183 per 100,000 population/year.1 The diagnosis of these patients in emergency care is based on an algorithm that includes the use of clinical probability scales, D-dimer levels, and compression ultrasound (CUS).2 When clinical probability is high, despite D-dimer levels, it is mandatory to perform a CUS examination to confirm or to discard the presence of a DVT.2 On the other hand, when the pre-test clinical probability (PTCP) is low or moderate, the diagnosis of DVT can be safely excluded with a normal D-dimer blood level, avoiding the need for CUS.2
From the Angiology and Vascular Surgery Unit, Bellvitge University Hospital. Author conflict of interest: none. Correspondence: Xavier Jimenez-Guiu, MD, Angiology and Vascular Surgery Unit, Bellvitge University Hospital, C/Feixa Llarga s/n, 08907 Hospitalet del Llobregat, Spain (e-mail: [email protected]). The editors and reviewers of this article have no relevant financial relationships to disclose per the Journal policy that requires reviewers to decline review of any manuscript for which they may have a conflict of interest. 2213-333X Copyright Ó 2019 by the Society for Vascular Surgery. Published by Elsevier Inc. https://doi.org/10.1016/j.jvsv.2019.11.015
Improvements in the diagnosis and treatment of DVTs during the last decades have enabled affected patients to be completely managed as outpatients, except for some particular cases.3 Despite these advancements, which clearly provide better and more convenient care for the patients, the emergency staff may be overwhelmed by the huge number of CUS examinations, which are sometimes unnecessary. To improve the accuracy of D-dimer as a marker of DVT, it has been proposed that cutoff values be adjusted by age.4-8 Most studies made these adjustments on the basis of a limited CUS examination that included only the femoropopliteal segment and not the infrapopliteal veins.5-8 None of the available evidence concerning age-adjusted D-dimer thresholds included examination of distal veins in the CUS examination protocol, and this might have biased their results. It is well known that acute lower limb DVTs may start anywhere in the venous system. They usually start in the calf veins and extend proximally. The diagnosis and management of these isolated distal DVTs (IDDVTs) are still under discussion,9 as is the role of D-dimer in the diagnostic algorithm. In 2014, a prospective study published by Sartori et al10 showed a false-negative rate of 14.4% for D-dimer in patients with acute IDDVT, although the timing between symptoms and the diagnosis was not 1
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reported and there was no clear differentiation between cases of acute DVT and chronic DVT. The need for treatment is uncertain with IDDVT; it should be considered because IDDVT has a potential risk (up to 15.5%) of proximal progression9,11 and a recurrence rate up to 18%,12 and pulmonary embolism (symptomatic and asymptomatic) is caused by IDDVT in up to 50% of patients.13-15 Present clinical guidelines recommend treating IDDVT with anticoagulation when it is symptomatic or has any of the following characteristics: the D-dimer level is abnormal; the thrombosis is extensive (>5 cm in length, involving multiple veins, or >7 mm in diameter); the patient has active cancer; there is a history of venous thromboembolism; the thrombosis is close to the proximal veins; or the provoking factor is not reversible.11 The goal of this study was to analyze the utility of age-adjusted D-dimer cutoff values in patients with clinically suspected DVT, including IDDVT, in an ambulatory setting.
METHODS We performed a prospective observational cohort study of 606 consecutive outpatients older than 18 years presenting to the emergency department between January and December 2016 with clinically suspected acute lower limb DVT (suspected by a family physician or emergency physician). Exclusion criteria were patients whose clinical onset occurred >15 days before (not acute DVT), refusal or inability of the patient to consent to the study, and patients currently being treated with anticoagulation. All patients were clinically assessed by a vascular surgeon, and the PTCP score was calculated (following Wells criteria16). We used the categorical variable of low, medium, or high PTCP because it is more accurate than the likely/unlikely classification and more useful because patients with a score of 2 can be classified as patients in whom D-dimer testing may be helpful, not requiring more diagnostic tools, whereas these patients require CUS when the two-level Wells rule is used. In all patients, we obtained D-dimer levels by turbidimetry technique with ACL TOP 550 (reagent D-Dimer HS; Instrumentation Laboratory, Bedford, Mass) with a Ddimer standard cutoff of 250 mg/L D-dimer units, which would be comparable to 500 mg/L fibrinogenequivalent units.17 We performed a complete CUS examination including femoral, popliteal, calf, peroneal, and tibial veins after the clinical evaluation and D-dimer test result. Lower limb venous CUS examination was performed by medical physicians of the Angiology and Vascular Surgery Unit using Philips Epiq 5 equipment (Philips Healthcare N.V., Best, The Netherlands) with a 510 MHz transducer for the infrainguinal area and a 3.5 MHz transducer for insonation of abdominal vessels. The examination was performed in a supine position for the femoropopliteal sector and in the standing or reverse Trendelenburg position for the distal area. The
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ARTICLE HIGHLIGHTS d
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Type of Research: Single-center prospective nonrandomized cohort study Key Findings: In patients with isolated distal deep venous thrombosis (DVT), a comparison was conducted of results of the common D-dimer threshold in 606 patients with low or moderate clinical suspicion of lower limb DVT (by Wells criteria) and the age-adjusted D-dimer threshold (D-dimer threshold ¼ age 10 mg/L). The sensitivity decreased from 93% to 76%, proving not to be a useful screening test. Take Home Message: The authors suggest that the age-adjusted D-dimer threshold is not useful in the diagnostic algorithm for DVT when distal veins are routinely scanned.
deep veins were examined using compression by the transducer on B mode in the cross-sectional view. Color flow was used to detect luminal filling defects, and Doppler tracings were also obtained to detect spontaneous flow and phasicity. The diagnosis was established using the following ultrasound criteria: no collapse or partial collapse of the vein lumen at transducer compression; thrombus visualization within the vein lumen; absence of spontaneous venous flow; absence of Doppler signal; and increase in vein diameter. At least two of these criteria had to be present for diagnosis of DVT. We looked for a new threshold of D-dimer using the same strategy as Douma et al18 to adjust the D-dimer level according to age in the algorithm to rule out pulmonary embolism. For this purpose, we divided patients older than 50 years into 10-year age groups. We constructed receiver operating characteristic (ROC) curves of the D-dimer test for each group to find the best threshold (defined as the value of D-dimer that gives more specificity while maintaining the maximum possible sensitivity). We considered oncologic patients as a possible confounding factor, so we performed the same analysis with nononcologic patients. Categorical variables were presented as the number of cases and percentages; continuous variables were presented as the mean and standard deviation or median and interquartile range. To assess possible relationships, we plotted the proportion of DVTs for each quantile of age. To assess the accuracy of the D-dimer cutoff value of 250 mg/L, we computed the sensitivity, specificity, and positive and negative predictive values. The same procedure was done to evaluate the age-adjusted Ddimer cutoff value (10 mg/L).19 Finally, to avoid population bias, we performed the first analysis without including IDDVTs to see whether our population results were similar to those reported in the literature.
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Fig 1. Flow diagram of the study. Of 836 patients with clinically suspected lower limb deep venous thrombosis (DVT), 205 had a high pre-test clinical probability (PTCP) of DVT and were excluded. Of the 631 left, 606 met the inclusion criteria. Of those patients, 565 did not had DVT and 41 did.
Because of the exploratory nature of the study in the analysis of the utility of age-adjusted D-dimer cutoff values in patients with clinically suspected DVT, sample size estimation was performed strictly on the basis of the maximum marginal error of estimate sensitivity. Values of sensitivity of age-adjusted D-dimer cutoff values and prevalence of DVT were hypothesized as 85% and 10%, respectively. In order for the maximum marginal error of estimate sensitivity not to exceed 7% with a 95% confidence level, the total required sample size was 600. A dropout rate of 15% was assumed.
The project was approved by the Investigation Ethics Committee of Hospital Universitari de Bellvitge (Reference PR421/17). The study was performed following the Helsinki Declaration consensus (Fortaleza, 2013). All data from patients were treated according to General Data Protection Regulation rules and Spanish laws LOPD 15/1999 and RD 1720/2007. All data were codified using a numeric code anonymously established for the purpose of this study. The investigation data were saved in an electronic directory with restricted access supervised by the Information Systems of Hospital Universitari de Bellvitge. Analyses were performed with R software 3.4.0.20
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Fig 2. Box plots showing patients with and without deep venous thrombosis (DVT) according to D-dimer levels and pre-test clinical probability (PTCP).
RESULTS Our study population included 249 men (41.1%) and 357 women (58.9%) with a mean age of 69.3 years, and 92 of these patients had an active neoplasm (15.2%). The Wells PTCP was moderate in 142 patients (23.4%) and low in 464 patients (76.6%; Fig 1). The D-dimer level of patients with low or moderate clinical probability of DVT was heterogeneous (Fig 2). Forty-one patients were diagnosed with DVT; the prevalence of DVT in the study group was 6.7%, and the proportion of DVT for each age group was homogeneous (Fig 3). The overall prevalence in our population (including high PTCP) was 26.8%. The most common area affected was distal (53.7%), followed by popliteal (29.3%), femoropopliteal (9.76%), and femoral (4.8%). One patient had an iliac DVT. Of the patients who had a DVT, 2.5% were in the low PTCP group and 20% were in the moderate PTCP group. At the threshold of 250 mg/L, global sensitivity was 93% (95% confidence interval [CI], 0.8-0.98) with a specificity of 8% (95% CI, 0.06-0.11), positive predictive value of 7% (95% CI, 0.05-0.09), and negative predictive value of 94% (95% CI, 0.83-0.99). Three patients had a D-dimer level below 250 mg/L but were diagnosed with DVT by CUS; one was femoral and two were distal. When the age-adjusted cutoff level was applied, global sensitivity was 76% (95% CI, 0.60-0.88), specificity was 61% (95% CI, 0.57-0.65), positive predictive value was 12% (95%
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CI, 0.09-0.17), and negative predictive value was 97% (95% CI, 0.95-0.99). The false-negative rate was 24%. Ten patients had a normal age-adjusted D-dimer cutoff level but were diagnosed with DVT by ultrasound. Of these 10 patients, 8 had a distal DVT and 2 had a proximal DVT. We separated patients older than 50 years into four 10-year age groups: 50 to 60 years, 60 to 70 years, 70 to 80 years, and >80 years. The optimum thresholds were 526 mg/L (sensitivity 100%, specificity 51%), 442.5 mg/L (sensitivity 100%, specificity 43%), 475 mg/L (sensitivity 81%, specificity 31%), and 549 mg/L (sensitivity 100%, specificity 55%), respectively (Fig 4; ROC curves for all patients are shown in Fig 5, A). We then performed the same analysis without cancer patients. Our nononcologic study population included a total of 514 patients. Of them, 405 patients (78.8%) had a low PTCP and 109 (21.2%) had a moderate PTCP. The prevalence of lower limb DVT was 6% (31 cases). The sectors affected were the distal sector (51.8%), followed by the popliteal (29%), femoral (6.4%), and finally the femoropopliteal and iliofemoral (3.2% each). The sensitivity of D-dimer with a classic threshold of 250 mg/L was 90% (95% CI, 0.74-0,98), with a specificity of 7% (95% CI, 0.05-0.10). The negative predictive value was 92% (95% CI, 0.79-0.98). Three patients were diagnosed with DVT by CUS but had a normal D-dimer level. When we applied the age-adjusted D-dimer cutoff level, the sensitivity was 74% (95% CI, 0.55-0.88) and the specificity was 61% (95% CI, 0.56-0.65). The negative predictive value was 97% (95% CI, 0.95-0.99), and the false-negative rate was 26%. Eight patients were diagnosed with DVT by CUS but had a normal age-adjusted D-dimer level; six DVTs were distal and two were proximal. After splitting patients older than 50 years in 10-year age groups, we obtained four groups: 50 to 60 years, 60 to 70 years, 70 to 80 years, and >80 years. The optimum thresholds were 523 mg/L (sensitivity 100%, specificity 48%), 442 mg/L (sensitivity 100%, specificity 44%), 641 mg/ L (sensitivity 71%, specificity 52%), and 763 mg/L (sensitivity 100%, specificity 71%), respectively (Fig 4; ROC curves for all patients are shown in Fig 5, B). We could not perform a linear regression (in all patients and in nononcologic patients) because the curve was a parabola and there was not a correlating regression line. On excluding IDDVTs and applying the age-adjusted D-dimer threshold, sensitivity was 89% (95% CI, 0.67-0.99) with a specificity of 61% (95% CI, 0.57-0.65), positive predictive value of 7% (95% CI, 0.04-0.11), and negative predictive value of 99% (95% CI, 0.98-1.00).
DISCUSSION
Fig 3. Distribution of deep venous thromboses (DVTs) among quantiles of age.
In this study, we found a lower sensitivity for the ageadjusted D-dimer cutoff level than with the normal threshold in patients with clinically suspected lower limb DVT when the calf and distal areas were included in the CUS examination. Treatment of IDDVT is still being debated, and clinical guidelines recommend treatment
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Fig 4. Optimum threshold for D-dimer level per age group (maintaining maximum sensitivity and highest possible specificity) in global population and in nononcologic patients. A similar analysis was performed by Douma et al18 to obtain the age-adjusted D-dimer level formula for pulmonary embolism. In our results, we can see that the progression of the best D-dimer threshold does not increase according to age. Moreover, it decreases in the 60- to 70-year and 70- to 80-year age groups compared with the 50- to 60-year age group.
with anticoagulation when patients are symptomatic or when extensive risk factors are present (grade 2C).11 Otherwise, a second CUS examination should be performed in 2 weeks (grade 2C) to see whether there has been proximal progression, following Chest Guidelines
2016 recommendations.11 These recommendations emphasize that there is not a consensus on IDDVT treatment. This is due to a lack of studies, especially randomized clinical trials, as all available studies are systematic reviews.21,22 Despite this, our multidisciplinary DVT team
Fig 5. Receiver operating characteristic (ROC) curves of the D-dimer test for each 10-year age group (A) and ROC curves of the D-dimer test for each 10-year age group without oncologic patients (B). In A, we represent ROC curves for each 10-year age group including all patients of the study. From those ROC curves, we obtained the optimum threshold for the D-dimer level of every age group to find a directly proportional relationship between D-dimer and age. The same happened when we excluded oncologic patients (to avoid a potential bias).
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always extends the CUS examination to distal veins to check for IDDVT, given their risk of recurrence (up to 18%)9,11 and progression (up to 15%),12 and because it is sometimes the first sign of an underlying disease. When we analyzed the inclusion and exclusion criteria in the published studies, the peroneal, tibial, and calf veins were not included in the CUS examinations. In 2010, Douma et al5 studied the results obtained in five different cohorts of patients. In one cohort, the CUS examination included the trifurcation of calf veins, but no veins below the knee veins were explored; in fact, the sectors affected were not described in the results of any of the cohorts. The same happened in the studies by Cini et al,7 Hamblin et al,6 and Takach Lapner et al,23 in which only the proximal areas were studied. In 2018, Gómez-Jabalera et al24 published a study similar to previous reports but looking for other possible thresholds (multiplying the age 10, 15, 20, 25, and 30 mg/L). The CUS protocol included calf veins but not peroneal or tibial veins. The sectors affected were not included in the results. Our results differ from those published in the reference studies,5-8,23-27 in which the false-negative rates were between 0% and 4.8% when the age-adjusted D-dimer level was applied. We had a 24% false-negative rate, which is surprisingly high compared with the 7% falsenegative rate for the classic cutoff level. We performed the analysis excluding IDDVTs to see whether our population differed from the reference studies, but results were similar to those published before. Our data suggest that the age-adjusted D-dimer cutoff value is not worthwhile when distal veins are scanned. The prevalence of DVT depends on the study population and the inclusion and exclusion criteria used in selection of patients. In published literature, the prevalence of DVT in the low-intermediate PTCP group (when Wells 1997 classification was applied) ranges from 4.2% to 51.6%. This indicates the heterogeneity of the studies. In our population, 2.5% of patients in the low PTCP group and 20% of patients in the moderate PTCP group were diagnosed with DVT. These prevalence values are similar to what Wells found in 1997 (prevalence of 3% for the low PTCP group and 16% for the moderate PTCP group). There are discrepancies in terms of reference ranges and clinical thresholds for the exclusion of thrombosis because there are many possible combinations between monoclonal antibodies and different assay reagents. In the reported studies, there is a wide difference in the tests used. Some authors used enzyme-linked immunosorbent assay (for example, with VIDAS [bioMérieux, Marcy-l’Étoile, France]5); others used second-generation latex agglutination techniques (like STA-Liatest [Diagnostica Stago, Asnières sur Seine, France]6); and in other studies, the D-dimer determination was made using a mix of different assays.5,27 Moreover, most of the time,
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these different laboratory tests are not validated prospectively on each population to determine the optimum threshold. Because of this heterogeneity of laboratory methods, we think that it is not proper to use the age-adjusted D-dimer threshold indiscriminately before validating your laboratory results and study population. Our study has been developed in a tertiary hospital that is the reference for an area of secondary and primary hospitals that have D-dimer as a tool before referring patients to us. That is why our population had mostly an abnormal D-dimer level. Despite having seven more false-negative results, there was an improvement of the negative predictive value from 94% to 97%. This is because the number of true negatives rose from 45 to 336 patients when the age-adjusted formula was applied. Even with negative predictive value outcomes, we think that leaving 10 patients undiagnosed is inadmissible because of the potential morbidity and mortality of DVTs. We performed an analysis similar to that of Douma et al18 to find the optimum number by which to multiply age to obtain a threshold with the maximum specificity without losing sensitivity. We found that the thresholds measured by ROC curves in 10-year age groups (in patients older than 50 years) were different from the ones found for pulmonary embolism. We did not find an ascending curve; in contrast, the optimal threshold rises from 525.6 mg/L in patients between 50 and 60 years old to 549.5 mg/L in patients older than 80 years and has a parabolic curve. We performed the same analysis in nononcologic patients and found similar results. These results call into question the relationship between the age-adjusted D-dimer level and DVT in patients with low and moderate PTCP. It also signifies the importance of validating our own D-dimer assays and reagents to obtain the optimum threshold for every reference population and of judging the requirement and utility of an age-adjusted threshold application. The main limitation of the study was that a quarter of patients arrived from smaller hospitals. Therefore, there could be a number of undiagnosed DVTs with use of clinical criteria different from ours. The small size of our sample also reflects the difficulty of studying this group of patients, in which the prevalence of DVT is low.
CONCLUSIONS The age-adjusted D-dimer cutoff level did not show linear progression among age groups in our series. Therefore, it is not useful in the diagnostic algorithm for DVT when distal veins are routinely scanned. We would like to thank Statistics Advisory Service at IDIBELL collaboration for their help with our analyses.
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AUTHOR CONTRIBUTIONS Conception and design: XJG, ARV, RVC Analysis and interpretation: XJG, ARV, MHS, CMR, RVC Data collection: XJG, ARV, MHS Writing the article: XJG, ARV, MHS Critical revision of the article: XJG, ARV, MHS, CMR, RVC Final approval of the article: XJG, ARV, MHS, CMR, RVC Statistical analysis: XJG, ARV Obtained funding: Not applicable Overall responsibility: XJG
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14. Hollerweger A, Macheiner P, Rettenbacher T, Gritzmann N. Sonographic diagnosis of thrombosis of the calf muscle veins and the risk of pulmonary embolism. Ultraschall Med 2000;21:66-72. 15. Ohgi S, Tachibana M, Ikebuchi M, Kanaoka Y, Maeda T, Mori T. Pulmonary embolism in patients with isolated soleal vein thrombosis. Angiology 1998;49:759-64. 16. Wells PS, Anderson DR, Bormanis J, Guy F, Mitchell M, Gray L. Value of assessment of pretest probability of deepvein thrombosis in clinical management. Lancet 1997;350: 1795-8. 17. Keeling DM, Mackie IJ, Moody A, Watson HG; Haemostasis and Thrombosis Task Force of the British Committee for Standards in Haematology. The diagnosis of deep vein thrombosis in symptomatic outpatients and the potential for clinical assessment and D-dimer assays to reduce the need for diagnostic imaging. Br J Haematol 2004;124:15-25. 18. Douma RA, le Gal G, Söhne M, Righini M, Kamphuisen PW, Perrier A, et al. Potential of an age adjusted D-dimer cut-off value to improve the exclusion of pulmonary embolism in older patients: a retrospective analysis of three large cohorts. BMJ 2010;340:1475. 19. Zhou XA, Obuchowski NA, McClish DK. Statistical methods in diagnostic medicine. 2nd ed. Hoboken, NJ: Wiley; 2011. 20. R Core Team. R: a language and environment for statistical computing. Vienna, Austria: R Foundation for Statistical Computing; 2018. 21. Masuda EM, Kistner RL, Musikasinthorn C, Liquido F, Geling O, He Q. The controversy of managing calf vein thrombosis. J Vasc Surg 2012;55:550-61. 22. De Martino RR, Wallaert JB, Rossi AP, Zbehlik AJ, Suckow B, Walsh DB. A meta-analysis of anticoagulation for calf deep venous thrombosis. J Vasc Surg 2012;56:228-37. 23. Takach Lapner S, Julian JA, Linkins LA, Bates SM, Kearon C. Questioning the use of an age-adjusted D-dimer threshold to exclude venous thromboembolism: analysis of individual patient data from two diagnostic studies. J Thromb Haemost 2016;14:1953-9. 24. Gómez-Jabalera E, Bellmunt Montoya S, Fuentes-Camps E, Escudero Rodríguez J. Age-adjusted D-dimer for the diagnosis of deep vein thrombosis. Phlebology 2018;33:1-6. 25. Legnani C, Cini M, Scarvelis D, Toulon P, Wu JR, Palareti G. Multicenter evaluation of a new quantitative highly sensitive D-dimer assay, the Hemosil D-dimer HS 500, in patients with clinically suspected venous thromboembolism. Thromb Res 2010;125:398-401. 26. Bates SM, Kearon C, Crowther M, Linkins L, O’Donnell M, Douketis J, et al. A diagnostic strategy involving a quantitative latex D-dimer assay reliably excludes deep venous thrombosis. Ann Intern Med 2003;138:787-94. 27. Mullier F, Vanpee D, Jamart J, Dubuc E, Bailly N, Douxfils J, et al. Comparison of five D-dimer reagents and application of an age-adjusted cut-off for the diagnosis of venous thromboembolism in emergency department. Blood Coagul Fibrinolysis 2014;25:309-15.
Submitted Aug 2, 2019; accepted Nov 18, 2019.