D-dimer Methods Research Articles

Using an age and fibrinogen levels adjusted D-dimer cutoff significantly improves the specificity of two equivalent D-dimer assays for excluding pulmonary embolism

ObjectivesOur single-center prospective study compared two methods of D-dimer determination used in the exclusion of pulmonary embolism: bioMérieux method, VIDAS® D-Dimer Exclusion™ II, and Diagnostica Stago method, STA®-Liatest® D-Di Plus. For each of these two methods, we calculated optimized variable cutoffs based on fibrinogen and/or age to improve the specificity of the methods. Patients – methods2530 patients admitted to the Emergency Department of the Brest University Hospital for suspected pulmonary embolism were included in this study. The comparison of the two methods was performed by calculating their different characteristics: sensitivity, specificity and negative predictive value for different cutoffs systems: fixed or age-adjusted according to Douma et al. An optimization of the variable cutoff according to age and fibrinogen was then performed. ResultsThe two methods VIDAS and STAGO are approximately equivalent in terms of performance even if the STAGO method presents a better specificity (57.1 %) at the fixed cutoff of 0.5 μg/mL. The adoption of age-adjusted, fibrinogen-adjusted or doubly-adjusted (age and fibrinogen) cutoffs, significantly improves the specificity of the tests without affecting their excellent sensitivity. These specificities peak respectively at 75.8 % and 76 % for the VIDAS and STAGO tests when using a doubly-adjusted, age and fibrinogen, cutoff, i.e. a gain in specificity of approximately 10 % compared with the age-adjusted cutoff of Douma et al. and of approximately 20 % compared with the fixed cutoff of 0.5 μg/mL. ConclusionAdopting an optimized variable cutoff based on fibrinogen and/or age significantly improves specificity of D-dimer methods for pulmonary embolism exclusion.

Impact of D-Dimer Assays Performed at Local Labs Vs. Central Laboratory in the Evaluation of Apex Trial Outcomes

Introduction: Elevated D-dimer levels are expected to represent both patients at high risk for venous thromboembolism (VTE), and those benefiting from extended-duration antithrombotic therapy. Using D-dimer testing as a method for enrichment strategy, the APEX trial compared the clinical benefit of extended-duration betrixaban therapy with enoxaparin standard of care (NEJM 375:534, 2016). D-dimer test results from the local laboratories at the enrollment sites were used for study outcome analyses based on a ≥ 2xULN value to identify subjects with elevated D-dimer (Cohort 1).Methods: Bloodsamples were collected from hospitalized medically ill patients (n=7,513) enrolled in the APEX study for D-dimer level analysis. A total of 27 differentD-dimer tests were used for D-dimer testing at the local laboratories. A duplicate sample was analyzed independently by a central laboratory using a single, quantitative method (STA-LITA-D-Di test). APEX study data are further analyzed using D-dimer test results obtained from the central laboratory and then compared with the D-dimer results obtained from the local laboratories.Results: Analysis of APEX D-dimer results from local vs central labs was performed in randomized subjects in the modified intention to treat (mITT) population (which consists of all subjects who were administered at least one dose of study drug) (n=7441).In this population 1,365 D-dimer results (18.3%) were discordant. The percent discordance of central and local lab D-dimer results in the betrixaban (670/3721) and enoxaparin (695/3720) arms were 18.0% and 18.7%, respectively. The event rates using ≥ 2X ULN D-dimer cutoff value showed significant differences between the two treatments when central lab D-dimer value was used (5.3% vs 7.6%, p=0.002) and with the local D-dimer (5.7% vs 7.2%, p=0.038), but less so with the latter test. Event rates in subjects designated as positive by central lab but negative by local lab (false negatives) in enoxaparin (21/302, 7%) vs betrixaban (9/313, 2.9%) groups were significantly different while in subjects identified as negative by central lab and positive by local lab (false positives), there were no differences in the overall event rates for enoxaparin (18/393, 4.6%) and betrixaban (17/357, 4.8%) groups. Further analysis of the data based on the type of local D-dimer method utilized suggested that 9/27 tests resulted in false negatives more than false positives.Conclusions: Variability in D-dimer testing as a prognostic indicator for VTE can significantly impact outcome evaluation in clinical trials. Standardization of D-dimer testing is necessary when utilizing the test for predictive enrichment of patient population. DisclosuresJennings:Portola Pharmaceuticals: Consultancy, Research Funding. Cohen:Portola: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Curnutte:Portola Pharmaceuticals, Inc.: Employment, Equity Ownership.

Point-of-Care Testing for D-Dimer in the Diagnosis of Venous Thromboembolism in Primary Care: A Narrative Review.

Venous thromboembolism (VTE) is regarded as a significant cause of mortality and disability, affecting 1–2 per 1000 people annually, presenting with a relatively wide range of symptoms, which can pose a diagnostic challenge. Historically, people in whom VTE is suspected will have been taken to hospital for diagnosis and treatment; however, a high proportion of patients are found not to have VTE. Concerns have been expressed about potential delays in treatment, with the risk of additional morbidity and disability, and death. Diagnostic strategies are typically based on the use of a clinical prediction rule to determine the pre-test probability, complemented with a measurement of D-dimer, with confirmation by imaging assessment. This narrative review explores the literature on the use of point-of-care testing (POCT) for the measurement of D-dimer, as part of a clinical decision rule, for the diagnosis of deep vein thrombosis (DVT) and pulmonary embolism (PE) in the primary care setting. In the two main prospective management (validation) studies that included D-dimer POCT or similar technologies, with a total cohort of 1600 participants, DVT was ruled out in 49% of patients, with a false negative rate of 1.4%, whereas PE was ruled out in 45% of patients, with a false negative rate of 1.5%. This suggests that uptake of POCT D-dimer in primary care has the potential to reduce the number of referrals to hospitals for imaging confirmatory investigation, with consequent cost savings. Thus, adopting POCT for D-dimer in primary care can offer clinical and cost benefits, particularly when quantitative POCT assays are being used. Furthermore, POCT should be undertaken in collaboration with the local laboratories to ensure the harmonisation of D-dimer methods and quality assurance to improve the diagnosis of VTE.

C0510: New High Sensitive LOCI D-Dimer Method for the Detection of Very Low Concentrations in Human Citrated Plasma*

C0510: New High Sensitive LOCI D-Dimer Method for the Detection of Very Low Concentrations in Human Citrated Plasma*

Evaluation of the Alere D-dimer test for point of care testing

The primary care regularly sees patients that have symptoms that could be due to thromboembolic diseases. It would be valuable to be able to rule out deep venous thrombosis or pulmonary embolism using Wells score and a negative D-dimer testing already at the primary care unit. This requires a validated D-dimer assay suitable for primary care use. We compared D-dimer results obtained with the new point of care analyzer Alere Triage(®) and the central hospital laboratory STA-R Evolution analyzer from the same patient samples (n = 102). We also calculated the total coefficient of variation (CV) for the Alere method. The two methods showed a good linear correlation (R(2) = 0.977) and a slope of 0.975. CV for the Alere D-dimer method was well below 10%. The study shows that the Alere D-dimer assay and the central laboratory standard assay show similar results. We suggest that the Alere D-dimer assay could be used in primary care in combination with Wells score to reduce referrals to the emergency unit.

Comparison of five point‐of‐care D‐dimer assays with the standard laboratory method

D-dimer (DD) assays are effective for the exclusion of deep-vein thrombosis (DVT), but point-of-care (POC) DD assays have not been fully evaluated. We have compared five POC DD assays (Pathfast, Cardiac, Vidas, Stratus and NycoCard) with our routine DD method (Tinaquant), testing 60 samples from patients with suspected DVT. Using 0.5 μg/mL as a cut-off value, four samples tested negative with Tinaquant were positive with Pathfast. There were no Tinaquant-positive samples tested negative with Pathfast, while the overall agreement (k = 0.81) was very good. Four samples were discrepant between Tinaquant and Cardiac (cut-off, 0.4 μg/mL), while k = 0.72. One of two Tinaquant-negative samples was shown to be positive for either Vidas (cut-off, 0.5 μg/mL) or Stratus (cut-off, 0.4 μg/mL), respectively. The agreement with Tinaquant was excellent for both Vidas (k = 0.92) and Stratus (k = 0.94). Total CV was <10% for all four assays. Eight samples (of 27) were negative with NycoCard although they were positive with Tinaquant, while CV was 41%. Vidas cannot be considered a POC assay because the sample has to be centrifuged before testing. Our findings have also shown that the use of NycoCard is inappropriate. Stratus and Pathfast have a similar analytical profile in comparison with the Tinaquant method. Cardiac is potentially less sensitive but may still be acceptable for use. It seems that the employment of these three assays for rapid bed-side analysis offers a possibility to adequately rule out DVT in outpatients within minutes after admission.

Age and gender specific cut-off values to improve the performance of d-dimer assays to predict the risk of venous thromboembolism recurrence

The Prolong study shows that continuing vitamin K antagonists (VKA) in patients with abnormal D-dimer (evaluated by a qualitative assay, Clearview Simplify D-dimer) results in a significant reduction of venous thromboembolism (VTE) recurrence. The present study retrospectively analyzes a subgroup of patients enrolled in the Prolong study with a view to calculate cut-off values for six quantitative D-dimer methods to predict the risk of VTE recurrence. We measured D-dimer levels by VIDAS D-dimer Exclusion (bioMerieux), STA Liatest D-dimer (DiagnosticaStago), HemosIL D-dimer and HemosIL D-dimer HS (Instrumentation Laboratory), Innovance D-dimer (Siemens) and AutoDimer (Trinity Biotech) in frozen plasma aliquots sampled 30±10days after VKA cessation in 390 patients enrolled in the Prolong study. During follow-up (562.7years), 28 patients had recurrent VTE (7.2%, 5.0% person-years). Since D-dimer levels are positively correlated with age and significantly lower in men, we calculated method-specific cut-off values according to age and gender. The HRs for VTE recurrence calculated using method-specific cut-off values based on age and gender are higher than those using cut-off values indicated by the manufacturers for VTE exclusion in symptomatic outpatients. These data suggest that method-specific cut-off values calculated according to patient age and gender can be more accurate in identifying patients at a higher risk for VTE recurrence. These method-specific cut-off values are being evaluated in the ongoing prospective management multicenter DULCIS study.

113: Evaluation of Three D-Dimer Methods Reveals Age-Stratified Thresholds Maintain High Negative Predictive Value for Excluding Pulmonary Embolism While Improving Specificity

Pulmonary embolism (PE) is a serious condition that can lead to death or significant morbidity. Thus PE is actively excluded in many patients presenting to the ED with vague complaints including pain and dyspnea. The high negative predictive value (NPV) of D-dimer can aid the clinician by excluding pulmonary embolism in patients at low risk of the disease. We conducted a clinical validation of two d-dimer assays: the Siemens Innovance, and the Biosite Triage and compared them with our current assay, the Siemens Advance. We also sought to assess whether more stringent criteria can safely be applied to younger patients suspected of PE to limit diagnostic imaging. We prospectively studied 1375 patients suspected of PE presenting to our emergency department (ED). ED physicians assessed clinical pretest probability for PE using the Modified Wells model. Patients with Wells score < 4.5 had a d-dimer blood test. Surplus specimens from a subset of our patients were used to generate d-dimer results with the Innovance and Triage assays. Patients with positive d-dimer test (Advance≥1.2μg/mL), meeting Kline Criteria, or at high likelihood for PE, received imaging, either CT pulmonary angiography (CTPA) or ventilation/perfusion (V/Q) scintigraphy. Radiologists were blinded to clinical score and d-dimer test results. PE positive patients had a positive CTPA or intermediate or high probability V/Q scan. Follow-up to exclude false negative results included phone calls and review of hospital and death records. Sensitivity, specificity, PPV and NPV were calculated at different d-dimer thresholds and age ranges. The agreement between the three d-dimer tests was determined using the Spearman Correlation statistic. The Triage and Innovance methods compared favorably with correlation statistics of r=0.88. The Advance method did not compare as well; r=0.48 versus Triage and 0.52 versus Innovance). The table (1st 3 lines) displays the very high NPV for all three assays, but shows the significantly (p< 0.001) improved specificity of both the Innovance and Triage assays compared with the Advance assay.Tabled 1 The 2nd half of the table shows that the cutoff values for excluding PE can be significantly increased for patients under age 50 while maintaining 100% NPV. This results in significantly higher specificity and thus decreased imaging (radiation exposure) and cost. Using cutoffs for the Innovance (0.5 μg/mL) and Triage (400 ng/mL) assays, 41.4% and 28.2% of patients would be imaged. When increasing the thresholds to 1.6 μg/mL (Innovance) and 800 ng/ml (Triage), 10.6% and 16.0% of patients would be imaged, respectively. For those under age 50, only 3.6% or 6.9% of patients (Innovance or Triage, respectively) would have been imaged. Innovance and Triage d-dimer assays result in excellent exclusion of PE while increasing specificity compared to the Advance assay. A higher d-dimer threshold can be safely applied to patients under age 50, resulting in fewer imaging studies, and significantly reducing hospital costs and radiation exposure.

Different cut-off values of quantitative D-dimer methods to predict the risk of venous thromboembolism recurrence: a post-hoc analysis of the PROLONG study

The PROLONG study showed that patients with venous thromboembolism who had qualitatively abnormal results in a D-dimer assay (Clearview Simplify D-dimer) after discontinuation of vitamin K antagonism benefit from resumption of treatment with vitamin K antagonism. The objective of this study was to evaluate the possible advantage of using quantitative D-dimer assays. VIDAS D-dimer Exclusion (bioMerieux), Innovance D-DIMER (Dade Behring), HemosIL D-dimer HS (Instrumentation Laboratory) and STA Liatest D-dimer (Diagnostica Stago) assays were performed in plasma aliquots sampled 30+/-10 days after cessation of vitamin K antagonism in 321 patients enrolled in the PROLONG study. During the follow-up without vitamin K antagonism, 25 patients had recurrent venous thromboembolism. The cut-off levels of the quantitative assays giving results most comparable with those of the qualitative test were: VIDAS = 800 ng/mL; Innovance = 800 ng/mL; HemosIL HS = 300 ng/mL; STA Liatest = 700 ng/mL. When the effect of the patients' age (< or = 70 vs. >70 years) was analyzed, it was found that only in younger patients was the rate of recurrence of venous thromboembolism significantly higher in patients with abnormal D-dimer levels. However, using the quantitative assays and age-specific cut-off levels it was possible to determine statistically significant hazard ratios also in elderly patients (VIDAS = 600 and 1200 ng/mL, Innovance = 500 and 900 ng/mL, HemosIL HS = 250 and 450 ng/mL, STA Liatest = 700 and 1000 ng/mL, in patients aged < or = 70 and >70 years, respectively). Quantitative D-dimer assays may provide information useful for evaluating the individual risk of recurrent venous thromboembolism. They seem particularly advantageous since they allow the selection of different cut-off levels according to the age or other characteristics of the patients.

A model for the harmonisation of test results of different quantitative D-dimer methods

The numerical test results of different D-dimer assays vary widely. Because of the complexity of the analyte of target as well as the variability in specificity of different D-dimer assays, only harmonisation of the test results seems to be feasible. The use of a single conversion factor does not take into account for several methods the lack of commutability between test results and consensus values at different D-dimer levels. This is probably related to the mutually different response of methods to high and low levels. We therefore designed a harmonisation model based on the transformation of a method-specific regression line to a reference regression line. We used the data for the measurement of a set of plasma samples with different D-dimer levels by 353 different laboratories using 7 of the most frequently used quantitative D-dimer methods. For each method we calculated the method-specific consensus value for each sample. The overall median value was also estimated. Per method linear regression was applied throughout the method-specific consensus values using the amount of patient pooled plasma added to the different plasma samples as the independent variable. The line through the overall median values of all 7 methods was used as the reference line. Harmonisation between the methods was obtained by transformation of the method-specific regression line to the reference line. This harmonisation resulted in a reduction of the variability between the method-specific consensus values from about 75% to about 5.5%. Clinical validation of this concept had shown significant improvement of the test result comparability. We conclude that this model is a feasible approach in the harmonisation of D-dimer methods. If the harmonisation procedure is included in the calibration procedure by the manufacturers, customers will automatically obtain harmonised test results.

D-dimer is not useful for the diagnosis of isolated superficial venous thrombosis

D-dimer is not useful for the diagnosis of isolated superficial venous thrombosis

The Harmonization of Quantitative Test Results of Different D-Dimer Methods

Nowadays D-dimer testing is frequently applied in the diagnosis of venous thromboembolism. However, the test results of different quantitative D-dimer tests can differ significantly. The background of this variability, which is mainly caused by the variety of fibrin degradation products in plasma, the specificity of D-dimer assays, and the calibrators used in the test, is summarized here. Because D-dimer is not a single entity in plasma but a mixture of heterogeneous fibrin degradation products, method standardization is in principle impossible. Efforts undertaken in the past to standardize D-dimer methods are summarized. All these projects failed and it was concluded that only harmonization of D-dimer test results seems to be feasible. The results of a large field study on which a new approach to the harmonization of quantitative D-dimer methods will be based is summarized in this article. This approach seems to be an adequate solution for overcoming the practical problem of variation of test outcome in different D-dimer assays.

The Clinical Utility of D-dimer Testing in Diagnosing Venous Thromboembolic Disease

The Clinical Utility of D-dimer Testing in Diagnosing Venous Thromboembolic Disease

Diagnostic Value of the D-Dimer Test in Deep Vein Thrombosis: Improved Results by a New Assay Method and by Using Discriminate Levels

Previous studies have suggested that D-dimer testing reliably selects patients for whom duplex sonography should be performed for diagnosis of deep vein thrombosis (DVT). However, the interassay correlation is poor. Therefore, we tested four D-dimer methods for their ability to rule out DVT, including the Miniquant test, a new D-dimer assay method. Sensitivity, specificity, negative predictive value (NPV) and positive predictive value (PPV) were calculated vs. duplex sonography. Twenty-nine of 108 (27%) patients with suspected DVT were diagnosed as having DVT by sonography. The Vidas enzyme-linked immunoabsorbent assay (ELISA) test, the Miniquant turbidimetric test and the latex agglutination test for D-dimer all provided discriminate values for achieving 100% sensitivity and 100% NPV. D-dimer results demonstrated higher specificity and PPV in the outpatient vs. the inpatient group. This probably reflects the higher proportion of inpatients with comorbid conditions, such as malignancy and postsurgery status, in whom D-dimer results show very poor specificity and PPV. The new Miniquant turbidimetric assay performed as well as the more established ELISA method. We conclude that the D-dimer tests were shown to possess the necessary sensitivity and NPV to be useful in screening patients with suspected DVT. A negative D-dimer test in selected patients could be helpful in reducing the number of sonograms performed for diagnosis of DVT.

Complexes between Activated Protein C and Protein C Inhibitor Measured with a New Method

A first clinical evaluation has been made of the performance of a newly devised immunofluorometric assay for measuring plasma concentrations of activated protein C (APC) in complex with protein C inhibitor (PCI). The method was compared with testing for other markers of hypercoagulability in a case-control study comprising 123 patients with clinical suspicion of deep vein thrombosis (DVT). The diagnosis was confirmed by ascending phlebography, and the thrombotic burden estimated with a newly developed scoring system. Receiver operating characteristics (ROC) curves calculated to demonstrate the discriminatory capacity of the methods, showed the area under the curves (AUCs) to be similar for the APC-PCI and D-dimer methods. However, in contrast to the D-dimer method, the APC-PCI method measures a well-defined analyte, a prerequisite for reliable comparisons of future clinical studies. The APC-PCI method appears to be particularly useful as a marker for detection of recently developed proximal thrombi.

Preliminary Evaluation of two New Rapid Immunoturbidimetric D-dimer Assays in Patients with Clinically Suspected Venous Thromboembolism (VTE)

The practical utility and diagnostic accuracy of two new rapid, automated and quantitative immunoturbidimetric D-dimer methods have been evaluated in a population of 123 randomly selected patients with suspected VTE. The STA Liatest D-dimer and MDA D-dimer methods are based on the photo-optical measurement of the rate of agglutination of antibody-coated latex particles. The VIDAS D-dimer automated Elisa was used as the reference method. Diagnosis was confirmed in 51 patients (29 PE, 19 DVT, 3 DVT+PE). The immunoturbidimetric methods compared favorably with the VIDAS Elisa as judged from the correlation coefficients of linear regression lines (r = 0.82, MDA vs VIDAS; r = 0.75, STA vs VIDAS) and areas under the curve of ROC plots (VIDAS 0.83; STA 0.83; MDA 0.81). At a discriminant value of 500 ng/mL, all three D-dimer assays showed high sensitivity (96-98%), high NPV (93-97%) and moderate specificity (39-42%). Reproducibility of results around the cut-off is an important aspect of the diagnostic utility of D-dimer assays. CV's of duplicate determinations in this critical zone showed average values of 5.4% and 17.0% for MDA and STA, respectively. These data demonstrate that such rapid and automated latex-based methods for the quantitative measurement of D-dimer hold promise as reliable and cost-efficient approaches for the exclusion of VTE. Prospective patient management studies will be required to confirm this.

Performance of semiquantitative and quantitative D-dimer assays in the ECAT external quality assessment program.

D-dimer levels are used in clinical practice as markers for the presence or exclusion of venous thrombosis. Therefore, it is important that the performance of the D-dimer tests is well controlled. One of the components of a laboratory quality program is external quality assessment (EQA). The main aim of EQA is to identify the degree of agreement among laboratories. In addition to identifying the individual laboratory performance, it also identifies the characteristics of the different reagents and methods that are used in different laboratories. Recently, the D-dimer test was included in the ECAT External Quality Assessment program. Eighty-one laboratories in four rounds applied semiquantitative and quantitative D-dimer assays to three samples (concentrations normal, slightly elevated, and elevated). Although the reported values varied widely, the classification of the samples was mostly correct for the normal and the elevated samples. The slightly elevated sample was classified as normal by all laboratories using semiquantitative methods and by 60% of the laboratories using quantitative methods, and this varied between 45% and 86% for the different methods. In conclusion, D-dimer methods show a large variation, and the quality of the D-dimer assessment could be improved by standardization and by using cut-off ranges.

Long-term influence of omega-3 fatty acids on fibrinolysis, fibrinogen, and serum lipids

The long-term influence of omega-3 fatty acids (ω-3 FA) on fibrinolytic parameters before and after venous occlusion (VO), fibrinogen, and serum lipids was assessed in a group of moderately hypertriglyceridemic patients undergoing coronary artery bypass surgery. The patients (n=58) were investigated before the operation (baseline), and 6 months afterwards. Following randomization postoperatively, 29 patients received 4g ω-3 FA concentrate, containing 3.4 g eicosapentaenoic and docosahexaenoic acid per day. The remaining 29 patients constituted the control group. Plasminogen activator inhibitor (PAI-1) activity had decreased in both groups at 6 months, whereas PAI-1 antigen increased in the ω-3 FA group and decreased in the control group (median change from baseline, 10.0% vs −12.9%, p=0.039). In both groups combined, there was a correlation between the change in PAI-1 antigen and the change in serum phospholipid ω-3 fatty acids (r=0.28, p=0.036). There was no group difference in tissue plasminogen activator activity and antigen, before as well as after VO. Global fibrinolytic activity after VO, assessed by the serum D-dimer method, was not statistically different in the two groups. Serum triglyceride levels were more reduced in the ω-3 FA group (median change from baseline, −34.5% vs −11.1% in the control group, p=0.001). There was no group difference in the concentrations of fibrinogen or cholesterol in lipoprotein fractions. Thus, an expected triglyceride-lowering effect by ω-3 FA was recorded, but except for an increase in PAI-1 antigen, no long-term influence on fibrinolytic parameters was noted.

Comparison of the Appropriateness of the Latex and Elisa Plasma &lt;i&gt;D&lt;/i&gt;-Dimer Determination for the Diagnosis of Deep Venous Thrombosis

Thirty-two patients suspected of deep venous thrombosis (DVT) of the leg were evaluated after simple plasma tests (latex D-dimer and Elisa D-dimer) against echography and phlebography as the gold standard of DVT. Seven patients showed negative results in the latter test. The classification conformity between the D-dimer methods amounted 84.4%. With regard to the diagnostic classification a high specificity of 100% was found for the latex D-dimer test at the cut-off level of 450 ng/ml, whereas for sensitivity, 96% was reached. The Elisa D-dimer test was striking by its high sensitivity of 100%, but its low specificity of 28.5%. In summary, these results demonstrate that when there is a suspicion of DVT according to the clinical symptoms, a negative latex test may reject the diagnosis, whereas the latex test is less useful to establish the diagnosis. On the contrary, the Elisa D-dimer test has a too high false-positive rate. The latex D-dimer test seems to be a reliable tool to exclude the diagnosis after which an ascending contrast venography can be omitted.