Review of D-dimer testing: Good, Bad, and Ugly.

D-dimer assays are commonly used in clinical practice to exclude a diagnosis of deep vein thrombosis or pulmonary embolism. More recently, they have been also been used to guide patients with unprovoked venous thromboembolism (VTE) when faced with the decision to continue or stop anticoagulation after initial treatment is complete. D-dimer assays vary widely with respect to the antibody used, method of capture, instrumentation required, and calibration standard. These differences have an important influence on the operating characteristics of the assays. Consequently, the evidence available in the literature for one assay cannot simply be extrapolated to another. In this review, we will outline the general properties of D-dimer assays, discuss the concept of raising the D-dimer threshold used in diagnosis of VTE according to pretest probability and age, and provide clinical perspective on the role of D-dimer testing in the diagnosis and prognosis of VTE.

Questioning the use of an age-adjusted D-dimer threshold to exclude venous thromboembolism: analysis of individual patient data from two diagnostic studies.

Essentials It is unclear if raising the D-dimer level to exclude venous thrombosis in older patients is valid. We compared this 'age-adjusted' strategy with other ways of interpreting D-dimer results. A non-age adjusted increase, and using higher thresholds in younger patients, was just as accurate. Age-adjustment of D-dimer thresholds does not appear to be appropriate. Click to hear Prof. le Gal's presentation on controversies in venous thromboembolism diagnosis SUMMARY: Background Using a progressively higher D-dimer level to exclude venous thromboembolism (VTE) with increasing age has been proposed but is not well validated. Objective To determine whether it is appropriate to use a progressively higher D-dimer level to exclude VTE with increasing age. Patients/methods We analyzed clinical data and blood samples from 1649 patients with a first suspected deep vein thrombosis or pulmonary embolism. We compared the negative predictive values (NPVs) for VTE, and the proportions of patients with a negative D-dimer result, by using three D-dimer interpretation strategies: a progressively higher D-dimer threshold with increasing age (age-adjusted strategy); the same higher D-dimer threshold in all patients (mean D-dimer strategy); and a progressively higher D-dimer threshold with decreasing age (inverse age-adjusted strategy). Results The NPV with the age-adjusted strategy (99.6%; 95% confidence interval [CI] 99.0-99.9%) was not different from that with the mean D-dimer strategy (99.7%; 95% CI 99.0-99.9%) or that with the inverse age-adjusted strategy (99.8%; 95% CI 99.1-99.9%). The proportion of patients with a negative result with the age-adjusted strategy (50.9%; 95% CI 48.5-53.4%) was not different from the proportion of patients with a negative result with the mean D-dimer strategy (51.7%; 95% CI 49.3-54.1%) or with the inverse age-adjusted strategy (49.5%; 95% CI 47.1-51.9%). Conclusions Our analysis does not support the use of a progressively higher D-dimer level to exclude VTE with increasing age.

Rivaroxaban for treatment of suspected or confirmed heparin-induced thrombocytopenia study.

UNLABELLED: Essentials Heparin-induced thrombocytopenia (HIT) is a thrombogenic condition that is difficult to treat. We evaluated rivaroxaban as a treatment option in patients with suspected or confirmed HIT. One patient had recurrent thrombosis and 9/10 patients with thrombocytopenia had platelet recovery. Rivaroxaban may be an effective and safe treatment option for HIT. SUMMARY: Background Rivaroxaban is a direct oral anti-Xa inhibitor that has the potential to greatly simplify treatment of heparin-induced thrombocytopenia (HIT). Objectives To evaluate the efficacy and safety of rivaroxaban in this patient population, we conducted a multicenter, single-arm, prospective cohort study of patients with suspected or confirmed HIT. Patients/Methods Twenty-two consecutive adults with suspected or confirmed HIT received rivaroxaban 15 mg bid until a local HIT assay result was available. Participants with a positive local assay result continued rivaroxaban 15 mg bid until platelet recovery (or until day 21 if they had acute thrombosis at study entry), then stepped down to rivaroxaban 20 mg daily until day 30. Results and Conclusions The primary outcome measure, incidence of new symptomatic, objectively-confirmed venous and arterial thromboembolism at 30 days, occurred in one HIT-positive participant (4.5%; 95% confidence interval [CI], 0-23.5%) and one HIT-positive participant required limb amputation despite platelet recovery. Platelet recovery was achieved in nine out of 10 HIT-positive patients with thrombocytopenia. Rivaroxaban appears to be effective for treating patients with confirmed HIT, although the small number of patients enrolled limits precision.

Rapid quantitative D-dimer to exclude pulmonary embolism: a prospective cohort management study.

UNLABELLED: ESSENTIALS: It is not known if D-dimer testing alone can safely exclude pulmonary embolism (PE). We studied the safety of using a quantitative latex agglutination D-dimer to exclude PE in 808 patients. 52% of patients with suspected PE had a negative D-dimer test and were followed for 3 months. The negative predictive value of D-dimer testing alone was 99.8%, suggesting it may safely exclude PE. BACKGROUND: Strategies are needed to exclude pulmonary embolism (PE) efficiently without the need for imaging tests. Although validated rules for clinical probability assessment can be combined with D-dimer testing to safely exclude PE, the rules can be complicated or partially subjective, which limits their use. OBJECTIVES: To determine if PE can be safely excluded in patients with a negative D-dimer without incorporating clinical probability assessment. PATIENTS/METHODS: We enrolled consecutive outpatients and inpatients with suspected PE from four tertiary care hospitals. All patients underwent D-dimer testing using the MDA D-dimer test, a quantitative latex agglutination assay. PE was excluded in patients with a D-dimer less than 750 µg FEU L(-1) without further testing. PATIENTS: with D-dimer levels of 750 µg FEU L(-1) or higher underwent standardized imaging tests for PE. All patients in whom PE was excluded had anticoagulant therapy withheld and were followed for 3 months for venous thromboembolism (VTE). Suspected events during follow-up were adjudicated centrally. RESULTS: Eight hundred and eight patients were enrolled, of whom 99 (12%) were diagnosed with VTE at presentation. Four hundred and twenty (52%) patients had a negative D-dimer level at presentation and were not treated with anticoagulants; of these, one had VTE during follow-up. The negative predictive value of D-dimer testing for PE was 99.8% (95% confidence interval, 98.7-99.9%). CONCLUSIONS: A negative latex agglutination D-dimer assay is seen in about one-half of patients with suspected PE and reliably excludes PE as a stand-alone test.

Recurrent venous thromboembolism in anticoagulated patients with cancer: management and short-term prognosis.

BACKGROUND: Recommendations for management of cancer-related venous thromboembolism (VTE) in patients already receiving anticoagulant therapy are based on low-quality evidence. This international registry sought to provide more information on outcomes after a breakthrough VTE in relation to anticoagulation strategies. METHODS: Patients with cancer and VTE despite anticoagulant therapy were reported to the registry. Data on treatments, VTE events, major bleeding, residual thrombosis symptoms and death were collected for the following 3 months. Breakthrough VTE and subsequent recurrences were objectively verified. Outcomes with different treatment strategies were compared with Cox proportional hazards regression. RESULTS: We registered 212 patients with breakthrough VTE. Of those, 59% had adenocarcinoma and 73% had known metastases. At the time of the breakthrough event, 70% were on low-molecular-weight heparin (LMWH) and 27% on a vitamin K antagonist (VKA); 70% had a therapeutic or supratherapeutic dose. After breakthrough the regimen was: unchanged therapeutic dose in 33%, dose increased in 31%, switched to another drug in 24%; and other management in 11%. During the following 3 months 11% had another VTE, 8% had major bleeding and 27% died. Of the survivors, 74% had residual thrombosis symptoms. Additional VTE recurrence was less common with LMWH than with a VKA (hazard ratio [HR], 0.28; 95% confidence interval [CI], 0.11-0.70) but similar with unchanged or increased anticoagulant intensity (HR, 1.09; 95% CI, 0.45-2.63). The bleeding rate did not increase significantly with dose escalation. CONCLUSION: Morbidity and mortality are high after recurrence of cancer-related VTE despite anticoagulation. Further treatment appears to be more effective with LMWH than with a VKA.

Use of different D-dimer levels to exclude venous thromboembolism depending on clinical pretest probability.

Currently, the same D-dimer cut-off point is used to define a positive result for all patients with suspected venous thromboembolism, regardless of their pretest probability. However, use of a relatively high D-dimer cut-off point (lower sensitivity) for those with a low clinical pretest probability, and a low D-dimer cut-off point (higher sensitivity) for those with a high clinical pretest probability, may be preferable. To determine if using three different D-dimer cut-off points according to low, moderate or high clinical pretest probability has greater utility for exclusion of venous thromboembolism than using the same single D-dimer cut-off point in all patients. Data from a previously published study of 571 patients was used to identify the highest D-dimer cut-off point with a negative predictive value of at least 98% for the subgroup of patients with low and high pretest probability. The D-dimer cut-off point for those with moderate clinical pretest probability remained unchanged [0.5 fibrinogen equivalent units (FEU) microgram mL(-1)]. Accuracy of D-dimer testing for venous thromboembolism using three cut-off points vs. one cut-off point was than determined. D-dimer cut-off points of 0.2 and 2.1 FEU microgram mL(-1) were selected for the high and low pretest probability groups, respectively. When three pretest probability-specific cut-off points were used instead of the previously determined single D-dimer cut-off point (0.5 FEU microgram mL(-1)), sensitivity and negative predictive value were unchanged (95 and 98%, respectively), but specificity increased from 44.7 to 60.4% (P < 0.001). This resulted in exclusion of venous thromboembolism in 80 additional patients. Use of three pretest probability-specific D-dimer cut-off points rather than a single D-dimer cut-off point for all patients, has the potential to increase the utility of D-dimer testing for the diagnosis of venous thromboembolism.

Monitoring the anticoagulant effect after a massive rivaroxaban overdose.

Rivaroxaban is a direct factor Xa inhibitor approved for prevention of stroke, prevention and treatment of venous thromboembolism and secondary prevention of acute coronary syndrome in many countries. As the use of this agent increases, so does the potential for overdose, both intentional and unintentional. Clinical data on overdoses of rivaroxaban in humans are limited. We report the case of a 42-year-old man who took an overdose of 1400 mg of rivaroxaban and describe how resolution of the anticoagulant effect was monitored using readily available coagulation assays.

Intracranial and fatal bleeding according to indication for long-term oral anticoagulant therapy.

BACKGROUND: Rate of major bleeding is generally accepted as a good measure of the risks associated with anticoagulant therapy, but this may not be true if the proportion of major bleeds with the most serious consequences differs according to the indication for anticoagulant therapy. OBJECTIVE: To determine whether the indication for long-term oral anticoagulant therapy influences the proportion of major bleeds that are intracranial and fatal. PATIENTS/METHODS: Two authors abstracted intracranial and fatal bleeds from randomized trials of patients who received anticoagulant therapy for a minimum of 6months for atrial fibrillation, ischemic heart disease, venous thromboembolism, prosthetic heart valves and ischemic stroke. RESULTS: There were 877 major bleeds among 23,518 patients in 39 studies. The proportion of bleeds that were intracranial was significantly higher in patients with ischemic stroke (36%; 95% CI, 22-52%; P=0.02) compared with patients with venous thromboembolism (10%; 95% CI, 5-20%). The difference in the proportion of bleeds that were intracranial among atrial fibrillation, ischemic heart disease, venous thromboembolism and prosthetic heart valves was not statistically significant; however, the estimates varied from 10% to 27%. The proportion of bleeds that were fatal did not differ significantly according to indication, but varied from 8% to 20%. For all indications for anticoagulation, intracranial bleeds were much more likely to be fatal than extracranial major bleeds (44% vs. 4% overall). CONCLUSIONS: In current practise, the indication for oral anticoagulant therapy has limited influence on the proportion of major bleeds that are intracranial or fatal.

Event adjudication and data monitoring in an intensive care unit observational study of thromboprophylaxis.

BACKGROUND: The objective of this report is to describe the roles, responsibilities and recommendations of a 3-member Event Adjudication Committee (EAC) and a 5-member data monitoring committee (DMC) for a prospective multicenter observational study of critically ill patients with renal insufficiency examining the bioaccumulation and bleeding risk associated with dalteparin thromboprophylaxis. METHODS: The EAC reviewed bleeding events to adjudicate whether they were major or minor and whether they were related to dalteparin (uncertain, unlikely, or likely). The DMC reviewed all bleeds deemed by the EAC as uncertain or likely due to dalteparin then recommended either to continue or suspend enrolment pending review by the steering committee, or requested more information. RESULTS: Consensus on bleeding severity was achieved for all cases. At the second planned interim analysis, the EAC recommended to the DMC and steering committee that the EAC should stop adjudicating whether bleeding was related to dalteparin since attribution was challenging in this population with numerous bleeding risk factors; moreover, no bleeding rates were available from prior studies or historical or concurrent controls. CONCLUSIONS: Adjudication of whether an outcome can be attributed to an intervention in an open-label, uncontrolled observational study gives a potentially misleading impression of research oversight without methodological face validity. In this study, the EAC recommended modification of the adjudication process, and the DMC recommended continuing enrolment to achieve the target sample size.

Differences in clinical presentation of deep vein thrombosis in men and women.

BACKGROUND: As assessment of clinical pretest probability is the first step in the diagnostic evaluation of deep vein thrombosis (DVT), it is important to know if the clinical features of DVT are the same in men and women. OBJECTIVES: To compare the prevalence and clinical characteristics of DVT, and the accuracy of clinical pretest probability assessment, between men and women with suspected DVT. METHODS: A retrospective analysis of individual patient data from three prospective studies by our group that evaluated diagnostic tests for a suspected first episode of DVT. Clinical characteristics, clinical pretest probability for DVT, and prevalence and extent of DVT was assessed in a total of 1838 outpatients. RESULTS: The overall prevalence of DVT was higher in men than in women (14.4% vs. 9.4%) (P = 0.001). The prevalence of DVT was higher in men than in women who were categorized as having a clinical pretest probability that was low (6.9% vs. 3.5%; P = 0.025) or moderate (16.9% vs. 8.7%; P = 0.04), but similar in patients in the high category (40.2% vs. 44.0%; P = 0.6). In patients diagnosed with DVT, swelling of the entire leg occurred more often (41.5% vs. 15.7%; P < 0.001), and thrombosis was more extensive (involvement of both popliteal and common femoral veins in 47.9% vs. 21.6%), in women than in men. CONCLUSIONS: In outpatients with suspected DVT, the overall prevalence of thrombosis and the prevalence of thrombosis in those with a low or a moderate clinical pretest probability were higher in men than in women.