A. J. ten Cate-Hoek

Is extensive screening for cancer in idiopathic venous thromboembolism warranted

Summary.  Background: Patients with a first episode of idiopathic venous thromboembolism (IVTE) have an estimated 10% incidence of cancer within 12 months after diagnosis. However, the utility of screening for cancer in this population is controversial. Methods: In this prospective concurrently controlled cohort study, limited and extensive cancer screening strategies were compared. All 630 patients underwent baseline screening consisting of history, physical examination, basic laboratory tests and chest X‐ray. In the extensive screening group abdominal and chest CT scan and mammography were added. Outcomes were incidence and curability of cancer, and cancer‐related and overall mortality. Results: In 12 of the 342 (3.5%) patients in the extensive screening group malignancy was diagnosed at baseline compared with 2.4% (seven of 288 patients) in the limited screening group. Extensive screening detected six additional cancers (2.0%; 95% CI, 0.74–4.3), of which three were potentially curable. During a median 2.5 years of follow‐up, cancer was diagnosed in 3.7% and 5.0% in the extensive and limited screening groups, respectively. In the extensive screening group 26 patients (7.6%) died compared with 24 (8.3%) in the limited screening group; adjusted hazard ratio 1.22 (95% CI, 0.69–2.22). Of these deaths 17 (5.0%) in the extensive screening group and 8 (2.8%) in the limited screening group were cancer related; adjusted hazard ratio 1.79 (95% CI, 0.74–4.35). Conclusions: The low yield of extensive screening and lack of survival benefit do not support routine screening for cancer with abdominal and chest CT scan and mammography in patients with a first episode of IVTE.

Management studies using a combination of D‐dimer test result and clinical probability to rule out venous thromboembolism: a systematic review

Summary.  Background: While the number of patients with suspected venous thromboembolism (VTE) referred to hospital emergency units increases, the proportion in whom the diagnosis can be confirmed is decreasing. A more efficient but safe diagnostic strategy is needed. Objective: To evaluate the safety of withholding anticoagulant therapy in patients suspected of VTE based on a diagnostic work‐up that combines a clinical decision rule (CDR) with a D‐dimer test result without performing additional diagnostic tests. Patients/methods: We searched Medline (January 1996–December 2004)‐related articles and reference lists of studies in English for prospective clinical studies that managed consecutive patients suspected of VTE and used a D‐dimer assay combined with an explicit CDR or implicit clinical judgment. Results: We identified 11 studies in which 6837 consecutive outpatients suspected of VTE were included. In the combined management studies, the overall rate of thromboembolic events was nine out of 2056 patients (0.44 %, 95% CI 0.2%–0.83%) in whom anticoagulants were withheld based on the D‐dimer result and a low clinical score. Similar results were obtained with qualitative and quantitative D‐dimer tests and with different decision rules. The rate of exclusion varied between 30% and 50% and was highest with a low incidence of VTE among those referred. Conclusion: Withholding anticoagulant treatment in patients suspected of VTE on the basis of a work‐up consisting of a low clinical probability combined with either a qualitative or quantitative D‐dimer test result is safe.

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.

Markers of coagulation, fibrinolysis and inflammation in relation to post-thrombotic syndrome.

Summary.  Background:  Post‐thrombotic syndrome (PTS) occurs in 20–50% of patients after a deep venous thrombosis (DVT). It is difficult to accurately predict which patients will develop PTS. Biomarkers could be a valuable tool for PTS risk assessment.

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

Summary.  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 €138 (

Cirrhosis patients have a coagulopathy that is associated with decreased clot formation capacity

185) per patient at the expense of a very small health loss (0.002 QALYs) compared with the best hospital strategy. The iCER is €55 753(

D-dimer as a marker for cardiovascular and arterial thrombotic events in patients with peripheral arterial disease. A systematic review.

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.

Biomarkers for post thrombotic syndrome: A case-control study

The coagulopathy in cirrhosis is associated with thrombosis and bleeding.

Post-thrombotic syndrome in patients treated with rivaroxaban or enoxaparin/vitamin K antagonists for acute deep-vein thrombosis A post-hoc analysis

Peripheral artery disease (PAD) is associated with an increased risk for cardiovascular events. D-dimers are a marker for hypercoagulability and are linked with thrombotic events in patients with venous as well as arterial thrombosis. The predictive value of plasma D-dimer levels in relation to cardiovascular events in patients with PAD is not unambiguously established. It was our objective to gather evidence evaluating the value of D-dimer as a predictor of arterial thrombotic events patients with PAD. The Pubmed, Embase, and Cochrane databases were searched (January 1980-November 2012), and 65 abstracts were found. The strategy was supplemented with manual review of reference lists. Case-control, cohort or prospective cohort studies that measured fibrin D-dimer in patients with PAD, were included. Studies were excluded if there was no follow-up for arterial thrombotic events or when no specific information on D-dimer was available. The search yielded 10 studies for our analysis, comprising 2,420 patients with PAD, with a total of 1,036 cardiovascular events in 10,599 patient-years. Two studies with a follow-up of one year showed that fibrin D-dimer predicts both deterioration of PAD and subsequent thrombotic events. Five out of six studies with a median follow-up of 2-4 years revealed that an increased D-dimer is predictive of various arterial thrombotic events including mortality. Two studies with a longer follow-up (over 6 years) did not show an independent association between increased D-dimer levels, arterial thrombotic events and CVD mortality. In conclusion, an increased D-dimer appeared to be independently associated with a two times increased risk of near-term cardiovascular events (relative risk 2.30, 95% confidence interval 1.43-3.68). However formal meta-analysis was only feasible for four out of 10 included studies. Due to the extended heterogeneity of the included studies cautious interpretation of these data is warranted.

Assessment of bleeding risk in patients with coronary artery disease on dual antiplatelet therapy. A systematic review.

INTRODUCTION There is limited knowledge on the etiology of post thrombotic syndrome (PTS), although several mechanisms have been proposed. The objectives are to explore the role of different pathogenic mechanisms for PTS, through measurement of an elaborate panel of biomarkers in patients with and without PTS. MATERIALS AND METHODS Patients with a history of deep vein thrombosis (DVT) with PTS (cases) and without PTS after minimal 2years follow-up (controls), were selected from the outpatient clinic of two Dutch hospitals. As a reference to the normal population healthy individuals (HI) without a history of venous thromboembolism were invited to participate. The population consisted of: 26 cases, 27 controls, and 26 HI. A panel of predefined biomarkers was measured in venous blood. RESULTS D-dimer showed a decreasing trend from cases to controls to HI; p=0.010. Thrombin/antithrombin complex levels were significantly higher in cases than in controls; p=0.032, and HI; p=0.017. APC-ratio was significantly lower in cases compared to controls; p=0.032, and HI; p=0.011. A significant trend of increasing proTAFI from cases, to controls, and HI; p=0.002 was found. There were no differences in inflammatory markers (CRP, Interleukin-6, Interleukin-8). Thrombomodulin, tissue-plasminogen activator, and von Willebrand factor were higher in patients compared to HI. There was a significant trend of decreasing sVCAM, from cases, to controls, and HI; p=0.029. CONCLUSIONS Patients with PTS displayed increased coagulation activity, an altered pattern of fibrinolytic marker expression, and increased endothelial activation. We found no evidence of systemic inflammation in patients with PTS at 63months since the last DVT.