Are the latest point-of-care D-dimer devices ready for use in general practice? A prospective clinical evaluation of five test systems with a capillary blood feature for suspected venous thromboembolism.

INTRODUCTION: We evaluated clinical performance of five novel point-of-care (POC) D-dimer devices with a capillary finger stick feature for predicting venous thromboembolism (VTE) in general practice: Exdia TRF Plus (E), AFIAS-1® (A), Standard F200® (S), LumiraDx™ (L) and Hipro AFS/1® (H). MATERIALS AND METHODS: Primary care patients with a low suspicion of a VTE were asked to consent to (i) draw additional venous blood samples, (ii) perform a capillary POC D-dimer test, (iii) approach their general practitioner afterwards for clinical outcomes. Venous plasma samples were processed on all POC devices and a laboratory-based assay (STA-Liatest®D-Di PLUS assay). Results were compared with clinical outcomes to generate performance characteristics. Capillary and venous blood results were used for a matrix comparison. RESULTS: Venous plasma samples from 511 participants, of whom 57 had VTE, were used for clinical performance analyses. Areas under Receiving Operating Characteristic Curves ranged from 0.90 (95 % CI: 0.86-0.94) (H) to 0.93 (0.90-0.96) (E). All false-negative rates were below 1.4 % (95 % CI: 0.5 %-3.4 %). Matrix comparison demonstrated correlation coefficients ranging from r = 0.11 (95 % CI: -0.15-0.36) (H) to r = 0.94 (0.90-0.97) (A) with concordance percentages ranging from 71.4 % (applying a D-dimer cutoff of 500 ng/mL) (H) to 100 % (applying an age-dependent D-dimer cutoff) (A). CONCLUSIONS: Clinical performance of the POC D-dimer devices for predicting a VTE in low-risk patients was comparable to that of a laboratory-based assay. However, our results indicate that the finger stick feature of certain devices should be further improved. (NL71809.028.19.).

Two point-of-care test-based approaches for the exclusion of deep vein thrombosis in general practice: a cost-effectiveness analysis.

BACKGROUND: In the diagnostic work-up of deep vein thrombosis (DVT), the use of point-of-care-test (POCT) D-dimer assays is emerging as a promising patient-friendly alternative to regular D-dimer assays, but their cost-effectiveness is unknown. We compared the cost-effectiveness of two POCT-based approaches to the most common, laboratory-based, situation. METHODS: A patient-level simulation model was developed to simulate the diagnostic trajectory of patients presenting with symptoms of DVT at the general practitioner (GP). Three strategies were defined for further diagnostic work-up: one based on current guidelines ('regular strategy') and two alternative approaches where a POCT for D-dimer is implemented at the 1) phlebotomy service ('DVT care pathway') and 2) GP practice ('fast-POCT strategy'). Probabilities, costs and health outcomes were obtained from the literature. Costs and effects were determined from a societal perspective over a time horizon of 6 months. Uncertainty in model outcomes was assessed with a one-way sensitivity analysis. RESULTS: The Quality-Adjusted Life Years (QALYs) scores for the three DVT diagnostic work-up strategies were all around 0.43 across a 6 month-time horizon. Cost-savings of the two POCT-based strategies compared to the regular strategy were €103/patient for the DVT care pathway (95% CI: -€117-89), and €87/patient for the fast-POCT strategy (95% CI: -€113-67). CONCLUSIONS: Point-of-care-based approaches result in similar health outcomes compared with regular strategy. Given their expected cost-savings and patient-friendly nature, we recommend implementing a D-dimer POCT device in the diagnostic DVT work-up.

Effectiveness of CHA2DS2-VASc based decision support on stroke prevention in atrial fibrillation: A cluster randomised trial in general practice.

BACKGROUND: Guidelines on atrial fibrillation (AF) recommend the CHA2DS2-VASc rule for anticoagulant decision-making, but underuse exists. We studied the impact of an automated decision support on stroke prevention in patients with AF in a cluster randomised trial in general practice. METHODS: Intervention practices were provided with a CHA2DS2-VASc based anticoagulant treatment recommendation. Reference practices provided care as usual. The primary outcome was incidence of ischaemic stroke, transient ischaemic attack (TIA) and/or thromboembolism (TE). Secondary outcomes were bleeding and the proportion of patients on guideline recommended anticoagulant treatment. RESULTS: In total, 1129 AF patients were included in the 19 intervention practices and 1226 AF patients in the 19 reference practices. The median age was 77 (interquartile range (IQR) 68-75) years, the median CHA2DS2-VASc score was 3.0 (IQR 2.0-5.0). Underuse of anticoagulants in patients with CHA2DS2-VASc score ≥ 2 was 6.6%. After a median follow-up of 2.7 years (IQR 2.3-3.0), the incidence rate per 100 person-years of ischaemic stroke/TIA/TE was 1.96 in the intervention group and 1.42 in the reference group (hazard ratio (HR) 1.3, 95% C.I. 0.8-2.1). No difference was observed in the rate of bleeding (0.79 versus 0.82), or in the underuse (7.2% versus 8.2%) or overuse (8.0% versus 7.9%) of anticoagulation. CONCLUSIONS: In this study in patients with AF in general practice, underuse of anticoagulants was relatively low. Providing practitioners with CHA2DS2-VASc based decision support did not result in a reduction in stroke incidence, affect bleeding risk or anticoagulant over- or underuse.

Exclusion of deep vein thrombosis using the Wells rule in clinically important subgroups: individual patient data meta-analysis.

OBJECTIVE: To assess the accuracy of the Wells rule for excluding deep vein thrombosis and whether this accuracy applies to different subgroups of patients. DESIGN: Meta-analysis of individual patient data. DATA SOURCES: Authors of 13 studies (n = 10,002) provided their datasets, and these individual patient data were merged into one dataset. ELIGIBILITY CRITERIA: Studies were eligible if they enrolled consecutive outpatients with suspected deep vein thrombosis, scored all variables of the Wells rule, and performed an appropriate reference standard. MAIN OUTCOME MEASURES: Multilevel logistic regression models, including an interaction term for each subgroup, were used to estimate differences in predicted probabilities of deep vein thrombosis by the Wells rule. In addition, D-dimer testing was added to assess differences in the ability to exclude deep vein thrombosis using an unlikely score on the Wells rule combined with a negative D-dimer test result. RESULTS: Overall, increasing scores on the Wells rule were associated with an increasing probability of having deep vein thrombosis. Estimated probabilities were almost twofold higher in patients with cancer, in patients with suspected recurrent events, and (to a lesser extent) in males. An unlikely score on the Wells rule (≤ 1) combined with a negative D-dimer test result was associated with an extremely low probability of deep vein thrombosis (1.2%, 95% confidence interval 0.7% to 1.8%). This combination occurred in 29% (95% confidence interval 20% to 40%) of patients. These findings were consistent in subgroups defined by type of D-dimer assay (quantitative or qualitative), sex, and care setting (primary or hospital care). For patients with cancer, the combination of an unlikely score on the Wells rule and a negative D-dimer test result occurred in only 9% of patients and was associated with a 2.2% probability of deep vein thrombosis being present. In patients with suspected recurrent events, only the modified Wells rule (adding one point for the previous event) is safe. CONCLUSION: Combined with a negative D-dimer test result (both quantitative and qualitative), deep vein thrombosis can be excluded in patients with an unlikely score on the Wells rule. This finding is true for both sexes, as well as for patients presenting in primary and hospital care. In patients with cancer, the combination is neither safe nor efficient. For patients with suspected recurrent disease, one extra point should be added to the rule to enable a safe exclusion.

Common alternative diagnoses in general practice when deep venous thrombosis is excluded.

BACKGROUND: In patients initially suspected of deep venous thrombosis (DVT) the diagnosis can be confirmed in approximately 10 to 30% of cases. For the majority of patients this means that eventually an alternative diagnosis is assigned. OBJECTIVE: To assess the frequency distribution of alternative diagnoses and subsequent management of patients in primary care after initial exclusion of DVT. In addition, assess the value of ultrasound examination for the allocation of alternative diagnoses. METHODS: Data were recorded by general practitioners alongside a diagnostic study in primary care in the Netherlands (AMUSE). Additional data were retrieved from a three-month follow-up questionnaire. A descriptive analysis was performed using these combined data. RESULTS: The most prevalent diagnoses were muscle rupture (18.5%), chronic venous insufficiency (CVI) (14.6%), erysipelas/cellulitis (12.6%) and superficial venous thrombosis (SVT) (10.9%). Alternative diagnoses were based mainly on physical examination; ultrasound examination (US) did not improve the diagnostic yield for the allocation of alternative diagnoses. In about 30% of all cases, a wait and see approach was used (27 to 41%). During the three-month follow-up nine patients were diagnosed with venous thromboembolic disease, three of which occurred in patients with the working diagnosis of SVT (p=0.026). CONCLUSIONS: We found that after exclusion of DVT in general practice a wait and see policy in the primary care setting is uneventful for almost one third of patients, but with the alternative diagnosis of SVT, patients may require closer surveillance since we found a significant association with thrombosis in these patients.

Systematic review: diagnostic accuracy of clinical decision rules for venous thromboembolism in elderly.

BACKGROUND: Physicians committed to the care of elderly patients, are challenged with the diagnosis of venous thromboembolism (VTE: deep venous thrombosis and pulmonary embolism) due to a higher incidence, co-morbidities masking signs and symptoms and burdening referrals. Clinical decision rules (CDRs) have been developed and implemented for VTE. Yet, until now, no study has evaluated the existing evidence of the diagnostic accuracy of CDRs for VTE in elderly. PURPOSE: To assess the effect of increasing age on diagnostic accuracy of CDRs for VTE in elderly. DATA SOURCES: A computerized systematic search was performed in Medline and Embase from 1950 to 2010. After checking reference lists and field experts, all key journals were hand searched. STUDY SELECTION: After review of 1538 eligible citations, nine articles were included and critically appraised on methodological quality by two reviewers using the QUADAS criteria. DATA EXTRACTION: Data on age subgroups, type of CDRs, sensitivity, specificity, safety, efficiency and the prevalence of deep venous thrombosis (DVT) and pulmonary embolism (PE) were extracted. DATA SYNTHESIS: Although sensitivity and safety of the CDRs for VTE in elderly remained high, the specificity and efficiency decreased substantially in older age groups. LIMITATIONS: A limited number of studies met our inclusion criteria. Possible referral bias due to inclusion of relatively high risk elderly patients. CONCLUSIONS: This diagnostic review demonstrates an increase of prevalence of PE with age and a strong decrease of specificity and efficiency for CDRs of VTE in older patients. Moreover, due to referral bias the decrease in specificity in the elderly may even be underestimated. Although the safety of CDRs for VTE is high, adapting these rules for elderly is much needed to make them more efficient for aged patients.

Cost-effectiveness of ruling out deep venous thrombosis in primary care versus care as usual.

BACKGROUND: Referral for ultrasound testing in all patients suspected of DVT is inefficient, because 80-90% have no DVT. OBJECTIVE: To assess the incremental cost-effectiveness of a diagnostic strategy to select patients at first presentation in primary care based on a point of care D-dimer test combined with a clinical decision rule (AMUSE strategy), compared with hospital-based strategies. PATIENTS/METHODS: A Markov-type cost-effectiveness model with a societal perspective and a 5-year time horizon was used to compare the AMUSE strategy with hospital-based strategies. Data were derived from the AMUSE study (2005-2007), the literature, and a direct survey of costs (2005-2007). RESULTS OF BASE-CASE ANALYSIS: Adherence to the AMUSE strategy on average results in savings of euro138 ($185) per patient at the expense of a very small health loss (0.002 QALYs) compared with the best hospital strategy. The iCER is euro55 753($74 848). The cost-effectiveness acceptability curves show that the AMUSE strategy has the highest probability of being cost-effective. RESULTS OF SENSITIVITY ANALYSIS: Results are sensitive to decreases in sensitivity of the diagnostic strategy, but are not sensitive to increase in age (range 30-80), the costs for health states, and events. CONCLUSION: A diagnostic management strategy based on a clinical decision rule and a point of care D-dimer assay to exclude DVT in primary care is not only safe, but also cost-effective as compared with hospital-based strategies.

Excluding venous thromboembolism using point of care D-dimer tests in outpatients: a diagnostic meta-analysis.

OBJECTIVE: To review the evidence on the diagnostic accuracy of the currently available point of care D-dimer tests for excluding venous thromboembolism. DESIGN: Systematic review of research on the accuracy of point of care D-dimer tests, using bivariate regression to examine sources of variation and to estimate sensitivity and specificity. DATA SOURCES: Studies on the diagnostic accuracy of point of care D-dimer tests published between January 1995 and September 2008 and available in either Medline or Embase. Review methods The analysis included studies that compared point of care D-dimer tests with predefined reference criteria for venous thromboembolism, enrolled consecutive outpatients, and allowed for construction of a 2x2 table. RESULTS: 23 studies (total number of patients 13 959, range in mean age 38-65 years, range of venous thromboembolism prevalence 4-51%) were included in the meta-analysis. The studies reported two qualitative point of care D-dimer tests (SimpliRED D-dimer (n=12) and Clearview Simplify D-dimer (n=7)) and two quantitative point of care D-dimer tests (Cardiac D-dimer (n=4) and Triage D-dimer (n=2)). Overall sensitivity ranged from 0.85 (95% confidence interval 0.78 to 0.90) to 0.96 (0.91 to 0.98) and overall specificity from 0.48 (0.33 to 0.62) to 0.74 (0.69 to 0.78). The two quantitative tests Cardiac D-dimer and Triage D-dimer scored most favourably. CONCLUSIONS: In outpatients suspected of venous thromboembolism, point of care D-dimer tests can contribute important information and guide patient management, notably in low risk patients (that is, those patients with a low score on a clinical decision rule).

A new diagnostic rule for deep vein thrombosis: safety and efficiency in clinically relevant subgroups.

BACKGROUND: Recently, a new, simple diagnostic rule was introduced to enable GPs to safely refrain from referring a considerable proportion of the patients suspected of having deep vein thrombosis (DVT). The rule (which includes seven patient history and physical examination items plus the result of a D-dimer test) discriminates 'very low' risk patients (not to be referred) from patients with an increased risk of DVT (to be referred). However, the rule's 'efficiency' (proportion of patients designated by the rule as very low risk) and safety (DVT prevalence among these very low risk patients) may change according to patient characteristics. OBJECTIVE: To test the rule's safety and efficiency in clinically relevant subgroups; i.e. across three age groups, in men and women, and in patients with and without a history of DVT, separately. METHODS: We retrospectively analysed data of 2086 primary care patients suspected of DVT, in whom all rule items and the result of the reference ('gold') standard (compression ultrasonography) were collected. RESULTS: The rule's efficiency decreased with age from 38.1% in the relatively young (<50 years) compared to 9.8% in patients aged > or =70 years. The percentage of DVT among the very low risk patients was <1.5% in all subgroups. The low efficiency in the elderly could be improved without compromising the safety by increasing the D-dimer threshold. CONCLUSION: The rule can safely exclude DVT in primary care patients suspected of DVT, irrespective of age, gender and history of DVT.

Excluding deep vein thrombosis safely in primary care.

Our validated primary care rule safely excludes deep vein thrombosis in one-quarter of patients suspected of having the disease. We recommend the use of this rule by family practitioners.

Exclusion and diagnosis of deep vein thrombosis in outpatients by sequential noninvasive tools.

Phlebography is the reference gold standard for the diagnosis of deep vein thrombosis (DVT), but due to its invasive nature and associated side effects it has been replaced by compression ultrasonography (CUS). Patients suspected of DVT are subjected to leg vein CUS that actually confirms DVT in only 16 to 28% of outpatients in large prospective management studies. CUS has a high positive predictive value of more than 98% for proximal DVT but usually misses calf vein thrombosis. Its negative predictive value for proximal DVT is about 97-98%, on the basis of which repeated scanning at day 7 after a negative first CUS (serial CUS) in outpatients with a first suspicion of DVT is advocated. Serial ultrasonography is costly and can be simplified and improved by the addition of clinical score and D-dimer testing. The safe exclusion of DVT by a rapid sensitive D-dimer test in combination with clinical score and/or CUS requires a negative predictive value of >99%. The negative predictive value for DVT is determined by the sensitivity of the rapid ELISA D-dimer test and the prevalence of DVT in subgroups of outpatients suspected of the condition. The prevalence of DVT in outpatients with a low, moderate and high clinical score varies widely from 3-10%, 15-30% and >70%, respectively. The combination of a low clinical score (prevalence DVT 3-5%) and a negative rapid ELISA D-dimer alone test will have a very high negative predictive value of >99.9% to exclude DVT without the need of CUS testing. The combination of a negative CUS and a negative rapid ELISA D-dimer test safely excludes DVT in patients with suspected DVT irrespective of the clinical score. The combination of a negative CUS, a low clinical score and a positive ELISA D-dimer but <1000 ng/ml excludes DVT with a negative predictive value of >99% without the need to repeat CUS. Patients with a negative CUS, scan but a positive ELISA D-dimer, and a moderate or high clinical score are still at risk with a probability of DVT of 3-5% and 20-30%, respectively and are thus candidates for repeated ultrasound scanning. The rapid ELISA D-dimer first followed by risk-based no, single or repeated CUS will be the most cost-effective strategy.