Johan Elf

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.

Clinical probability assessment and D-dimer determination in patients with suspected deep vein thrombosis, a prospective multicenter management study.

OBJECTIVES To investigate the reliability of a combined strategy of clinical assessment score followed by a local D-dimer test to exclude deep vein thrombosis. For comparison D-dimer was analysed post hoc and batchwise at a coagulation laboratory. DESIGN Prospective multicenter management study. SETTING Seven hospitals in southern Sweden. SUBJECTS 357 patients with a suspected first episode of deep vein thrombosis (DVT) were prospectively recruited and pre-test probability score (Wells score) was estimated by the emergency physician. If categorized as low pre-test probability, D-dimer was analysed and if negative, DVT was considered to be ruled out. The primary outcome was recurrent venous thromboembolism (VTE) during 3 months of follow up. RESULTS Prevalence of DVT was 23.5% (84/357). A low pre-test probability and a negative D-dimer result at inclusion was found in 31% (110/357) of the patients of whom one (0.9%, [95% CI 0.02-4.96]) had a VTE at follow up. Sensitivity, specificity, negative predictive value and negative likelihood ratio for our local D-dimer test in the low probability group were 85.7%, 74.5%, 98.2%, and 0,19 respectively compared to 85.6%, 67,6%, 97.9% and 0,23 using batchwise analysis at a coagulation laboratory. CONCLUSION Pre-test probability score and D-dimer safely rule out DVT in about 30% of outpatients with a suspected first episode of DVT. One out of 110 patients was diagnosed with DVT during follow up. No significant difference in diagnostic performance was seen between local D-dimer test and the post hoc batch analysis with the same reagent in the low probability group.

Diagnostic potential of plasma microRNA signatures in patients with deep-vein thrombosis

For excluding deep-vein thrombosis (DVT), a negative D-dimer and low clinical probability are used to rule out DVT. Circulating microRNAs (miRNAs) are stably present in the plasma, serum and other body fluids. Their diagnostic function has been investigated in many diseases but not in DVT. The aims of present study were to assess the diagnostic ability of plasma miRNAs in DVT and to examine their correlation with known markers of hypercoagulability, such as D-dimer and APC-PCI complex. Plasma samples were obtained from 238 patients (aged 16-95 years) with suspected DVT included in a prospective multicentre management study (SCORE). We first performed miRNA screening of plasma samples from three plasma pools containing plasma from 12 patients with DVT and three plasma pools containing plasma from 12 patients without DVT using a microRNA Ready-to-use PCR Panel comprising 742 miRNA primer sets. Thirteen miRNAs that differentially expressed were further investigated by quantitative real-time (qRT)-PCR in the entire cohort. The plasma level of miR-424-5p (p=0.01) were significantly higher, whereas the levels of miR-136-5p (p=0.03) were significantly lower in DVT patients compared to patients without DVT. Receiver-operating characteristic curve analysis showed the area under the curve (AUC) values of 0.63 for miR-424-5p and 0.60 for miR-136-5p. The plasma level of miR-424-5p was associated with both D-dimer and APC-PCI complex levels (p<0.0001 and p=0.001, respectively). In conclusions, these findings indicate that certain miRNAs are associated with DVT and markers of hypercoagulability, though their diagnostic abilities are probably too low.

The diagnostic performance of APC–PCI complex determination compared to d-dimer in the diagnosis of deep vein thrombosis

Abstractd-dimer testing is widely used as part of the diagnostic algorithm for the exclusion of deep vein thrombosis (DVT) but is considered of limited in value for ruling DVT in. Since d-dimers are poorly defined, there is no standardization of the assays and this makes reliable comparisons between clinical studies difficult. We report on a performance evaluation of a new marker of activated coagulation (Activated Protein-C in complex with Protein-C inhibitor, APC–PCI complex) compared to two quantitative d-dimer assays (Vidas®d-dimer Exclusion™and Autodimer®). The post-hoc comparison was made on 350 frozen plasma samples from consecutive outpatients suspected of DVT in a multicenter management study including clinical probability score, d-dimer testing, venous ultrasound and contrast venography as part of the diagnostic algorithm. Results: The APC–PCI complex performed inferior to the d-dimer assays in terms of sensitivity: 74 vs. >93%, negative predictive value: 91 vs. >96% and area under the curve: 0.82 vs. 0.9, but showed a significantly higher specificity: 80 vs. 40–60%. Specificity for the APC–PCI complex did not decrease with higher clinical probability score and the positive predictive value was significantly higher than that of the d-dimer assays in the intermediate/high probability cohort (66 vs. <52%). In this probability cohort, high levels of the APC–PCI complex and to a lesser extent, d-dimers, can give positive predictive values of >90% in up to 20% of the patients which indicates important clinical implications. However, for the exclusion of DVT at the pre-specified cut-off level, the APC–PCI complex perform inferior to the d-dimer assays in this study.

Performance of two relatively new quantitative D-dimer assays (Innovance D-dimer and AxSYM D-dimer) for the exclusion of deep vein thrombosis.

INTRODUCTION D-dimer assays are now widely used as the first-line test in the diagnostic algorithm of suspected deep vein thrombosis (DVT). The aim of this study was to evaluate the performance of two relatively new quantitative D-Dimer assays (Innovance and AxSYM) by comparison with a clinical gold standard. PATIENTS AND METHODS 311 samples from outpatients with clinical suspicion of DVT, included in a prospective management study, was analysed (prevalence of DVT 23%). The diagnostic workup included estimation of pre-test probability, D-dimer determination, objective imaging as well as 3 month clinical follow up of negative patients. RESULTS No significant differences were seen in sensitivity and negative predictive values between Innovance, AxSYM and the reference assays. The area under the ROC curve was slightly lower for the AxSYM assay and the correlation to the reference assays was only moderate (r < 0.8) whereas the agreement with the Vidas assay was near excellent (kappa = 0.8). The Innovance assay reached the highest AUC, showed a strong correlation with the reference assays (r > or = 0.9) and a good agreement with the Vidas assay (kappa = 0.76). In combination with a low pre-test probability score the Innovance assay reached a NPV of 100% (95% CI, 92-100) and the AxSYM assay 98% (95% CI, 87-100). CONCLUSION The Innovance and AxSYM assays show an overall good and comparable performance for the exclusion of DVT when compared to the established assays. Our results for the AxSYM assay indicate that the optimal cut-off value needs to be further evaluated.

A Cost-effectiveness Analysis of Diagnostic Algorithms of Deep Vein Thrombosis at the Emergency Department

INTRODUCTION Suspected cases of deep vein thrombosis are common at emergency departments and they often require extensive and costly diagnostic testing. The objective of this study was to evaluate whether a diagnostic algorithm based upon pre-test probability and D-dimer in diagnosing deep vein thrombosis may be cost-effective from a societal perspective in a Swedish setting. MATERIAL AND METHODS The cost-effectiveness of two alternative diagnostic algorithms were calculated using decision analysis. An algorithm which out ruled deep vein thrombosis among low probability patients with negative D-dimer was compared to a traditional algorithm including compression ultrasonography and/or contrast venography for all patients. For sensitivity analysis, a third reversed algorithm, where D-dimer was followed by pre-test probability, was analyzed. Estimates of probabilities were obtained from a prospective management study, including 357 outpatients with clinical suspicion of deep vein thrombosis. Direct costs were estimated using prices from Scania, Sweden. Indirect costs were estimated using time spent at the local emergency department and gross average wages in Sweden. RESULTS The total cost of the pre-test probability and D-dimer algorithm was estimated to euro406 per patient and the traditional algorithm was estimated to euro581 per patient. Reversing the order of the score and test resulted in an estimate of euro421 per patient. CONCLUSION At no significant difference in diagnostic efficacy the algorithm based upon pre-test probability and D-dimer was cost-effective, while the reversed algorithm and diagnostic imaging for all patients were not.

Identification of novel diagnostic biomarkers for deep venous thrombosis

The combination of a negative D‐dimer and a Wells score can rule out, but not confirm, a diagnosis of deep venous thrombosis (DVT). We aimed to identify new diagnostic biomarkers for DVT and to investigate their relationship with hypercoagulability markers [D‐dimer and activated protein C‐protein C inhibitor (APC‐PCI) complex]. We screened 92 cardiovascular‐specific proteins in plasma samples from 45 confirmed DVT patients and 45 age‐ and sex‐matched non‐DVT patients selected from a prospective multicentre diagnostic management study (SCORE) by Proseek Multiplex CVDIII96×96. Plasma levels of 30 proteins were significantly different between DVT and non‐DVT patients. After Bonferroni correction, plasma levels of seven proteins: P‐selectin, transferrin receptor protein 1, von Willebrand factor, tissue factor pathway inhibitor, osteopontin (OPN), bleomycin hydrolase and ST2 protein remained significantly different. The area under curve (AUC) for these proteins ranged from 0·70 to 0·84. Furthermore, all seven identified proteins were significantly associated with markers of hypercoagulability. A combination of OPN and APC‐PCI had the best ability to discriminate DVT from non‐DVT patients (AUC = 0·94; sensitivity = 89% and specificity = s84%). In conclusion, we identified multiple proteins associated with markers of hypercoagulability and with a potential to become novel diagnostic biomarkers for DVT.

The effects of baroreflex activation therapy on blood pressure and sympathetic function in patients with refractory hypertension: the rationale and design of the Nordic BAT study*

Abstract Objective: To explore the effects of baroreflex activation therapy (BAT) on hypertension in patients with treatment resistant or refractory hypertension. Methods: This investigator-initiated randomized, double-blind, 1:1 parallel-design clinical trial will include 100 patients with refractory hypertension from 6 tertiary referral hypertension centers in the Nordic countries. A Barostim Neo System will be implanted and after 1 month patients will be randomized to either BAT for 16 months or continuous pharmacotherapy (BAT off) for 8 months followed by BAT for 8 months. A second randomization will take place after 16 months to BAT or BAT off for 3 months. Eligible patients have a daytime systolic ambulatory blood pressure (ABPM) of  ≥145 mm Hg, and/or a daytime diastolic ABPM of  ≥95 mm Hg after witnessed drug intake (including  ≥3 antihypertensive drugs, preferably including a diuretic). Results: The primary end point is the reduction in 24-hour systolic ABPM by BAT at 8 months, as compared to pharmacotherapy. Secondary and tertiary endpoints are effects of BAT on home and office blood pressures, measures of indices of cardiac and vascular structure and function during follow-up, and safety. Conclusions: This academic initiative will increase the understanding of mechanisms and role of BAT in the refractory hypertension.

Improved Prognosis and Low Failure Rate with Anticoagulation as First-Line Therapy in Mesenteric Venous Thrombosis

BackgroundMonotherapy with anticoagulation has been considered as first-line therapy in patients with mesenteric venous thrombosis (MVT). The aim of this study was to evaluate outcome, prognostic factors, and failure rate of anticoagulation as monotherapy, and to identify when bowel resection was needed.MethodsRetrospective study of consecutive patients with MVT diagnosed between 2000 and 2015.ResultsThe overall incidence rate of MVT was 1.3/100,000 person-years. Among 120 patients, seven died due to autopsy-verified MVT without bowel resection and 15 underwent immediate bowel resection without prior anticoagulation therapy. The remaining 98 patients received anticoagulation monotherapy, whereof 83 (85%) were treated successfully. Fifteen patients failed on anticoagulation monotherapy, of whom seven underwent bowel resection and eight endovascular therapy. Endovascular therapy was followed by bowel resection in three patients. Two late bowel resections were performed due to intestinal stricture. The 30-day mortality rate was 19.0% in the former (2000–2007) and 3.2% in the latter (2008–2015) part of the study period (p = 0.006). Age ≥75 years (OR 12.4, 95% CI [2.5–60.3]), management during the former as opposed to the latter time period (OR 8.4, 95% CI [1.3–54.7]), and renal insufficiency at admission (OR 8.0, 95% CI [1.2–51.6]) were independently associated with increased mortality in multivariable analysis.ConclusionsShort-term prognosis in patients with MVT has improved. Contemporary data show that monotherapy with anticoagulation is an effective first choice in MVT patients.

Evaluation of direct oral anticoagulants and vitamin K antagonists in mesenteric venous thrombosis

Background/aim Mesenteric venous thrombosis is a rare lethal disease. The main aim of the present study was to evaluate clinical efficacy and safety of direct oral anticoagulants and vitamin K antagonists in mesenteric venous thrombosis patients. Methods Retrospective study of 102 mesenteric venous thrombosis patients treated between 2004 and 2017 at a center with a conservative medical first approach. Median clinical follow-up was 4 years. Results Computed tomography showed successful recanalization of thrombosis in 71% of patients on vitamin K antagonists and 69% of patients on direct oral anticoagulants (p = 0.88). Overall major and esophageal variceal bleeding rate was 14.7% and 2.9%, respectively. No difference in major bleeding (p = 0.54) was found between vitamin K antagonists and direct oral anticoagulants. No mesenteric venous thrombosis recurrence occurred during follow-up, and one venous thromboembolism occurred after cessation of anticoagulation. Conclusion Anticoagulation with direct oral anticoagulants and vitamin K antagonists was efficient in patients with mesenteric venous thrombosis. Bleeding complications was a concern during treatment in both groups.