Arina J. ten Cate-Hoek

Safely Ruling Out Deep Venous Thrombosis in Primary Care

Context Primary care physicians need office-based methods to rule out suspected deep venous thrombosis (DVT). Contribution The authors conducted a management trial of a prediction rule that uses clinical findings and a point-of-care d-dimer test to identify patients at very low risk for suspected DVT. They managed 1028 patients from approximately 300 primary care practices according to the rule, which identified nearly half (49%) to be at low enough risk to withhold imaging tests and anticoagulation treatment. In 3 months, 1.4% (95% CI, 0.6% to 2.9%) of low-risk patients had venous thromboembolism. Caution There was no control group. Authors relied on symptoms to detect subsequent venous thromboembolism. Implication Office-based methods can safely rule out DVT. The Editors Each year, more than 140000 persons in the United Kingdom present to their primary care physician with signs and symptoms suggestive of deep venous thrombosis (DVT) of the leg (1, 2). Because DVT is a potentially life-threatening disorder, current practice is to refer all patients for diagnostic testing services. These services are readily available, use noninvasive tests (such as, ultrasonography and d-dimer testing), and provide the referring physician with the assurance that DVT is not missed (3, 4). However, many studies have revealed that 80% to 90% of these referred patients do not have DVT (46). Therefore, it would be ideal to safely exclude DVT at initial presentation in a large proportion of these patients and thereby avoid referral. The recent introduction of rapid point-of-care d-dimer assays that can be included in a specific clinical decision rule makes it possible to do a diagnostic work-up in a primary care setting (79). We recently found that the use of a decision ruleinitially developed and validated in secondary carewas not accurate enough for primary care patients suspected of having DVT because the prevalence of thrombosis was still 2.9% among patients with a low probability (based on the Wells score and a normal quantitative d-dimer) compared with 0.9% reported in the original publication by Wells and colleagues (10, 11). Therefore, we developed and validated such a decision rule specifically for the primary care setting (10, 12) that included clinical items and the d-dimer assay result. A major difference between the rules, taking into account the additional use of d-dimer for low-probability patients in the Wells rule, is the replacement of the subjective phrase alternative diagnosis more likely with the more objective phrase absence of leg trauma. In primary care, the category of low probability based on the new rule had a 0.7% prevalence for thrombosis (13). However, as Reilly and Evans (14) recently outlined, development and validation studies should be followed by a prospective impact or management study demonstrating that the rule could be used by physicians to direct care before the rule is implemented in daily practice. Therefore, we conducted this study in a large series of consecutive patients in a primary care setting to evaluate the safety and efficiency of excluding DVT by using a clinical decision rule and a point-of-care d-dimer assay. In addition, we measured the yield of ultrasonography in the referred patients. Methods Study Overview In this prospective study in primary care, we managed patients suspected of having DVT by using a clinical decision rule that included a point-of-care d-dimer test. We did not refer patients with a low probability of DVT for further testing or administer treatment; we followed them for 3 months to record the incidence of venous thromboembolism (10, 12). Setting and Patients We invited the affiliated general practices of the 3 academic centers (who organized the study) to participate. Approximately 300 general practitioners agreed to participate. From March 2005 to January 2007, consecutive patients who presented with clinically suspected DVT were eligible for the study on the basis of the presence of at least 1 of 3 lower extremity symptoms: swelling, redness, or pain. We excluded patients if they were younger than 18 years, received anticoagulant treatment (that is, vitamin K antagonists or low-molecular-weight heparin) at presentation, or declined to participate. We obtained written informed consent, and the local institutional review boards approved the study. Diagnostic Strategy General practitioners applied a clinical decision rule, provided on a worksheet, to all study patients. This clinical decision rule was developed to safely exclude clinically suspected DVT in primary care patients. It included clinical items and a d-dimer assay result (Table 1) (10, 12). Table 1. Clinical Decision Rule Because we aimed to improve the management of patients suspected of having DVT in a primary care setting, we explicitly selected a rapid point-of-care d-dimer assay (Clearview Simplify d-dimer assay, Inverness Medical, Bedford, United Kingdom) (8, 15, 16). This allowed the general practitioner to use the decision rule outside of office hours and during house calls. We drew a capillary blood sample by using the finger-prick method (15). The test result was considered abnormal if, next to the control band, a second band appeared within 10 minutes (15). Participating physicians and their assistants received a single, brief instruction on how to use the d-dimer assay and the clinical rule. Physicians calculated the score for each patient by using the clinical decision rule (Table 1) (10, 12) and managed patients accordingly. Those with a score of 3 or less did not receive anticoagulant treatment or a referral for ultrasonography, but they were instructed to contact their general practitioner if symptoms became worse. Patients with a score of 4 or greater received a referral for ultrasonography. Deep venous thrombosis was considered present when 1 of the proximal veins of the lower extremities was noncompressible on ultrasonography (4). All patients visited their general practitioner between days 5 and 9 for reevaluation. Three months after entering the study, all patients received a questionnaire addressing signs and symptoms of (recurrent) venous thromboembolism. We contacted patients who did not respond (30%) through their general practitioners. If we had any suspicion of a (recurrent) venous thromboembolic event during the 3-month follow-up, based on the information presented in the questionnaire, we retrieved additional medical information of patients from their general practitioners, including letters from hospital specialists. Outcome Measure We defined the primary outcome as the incidence of symptomatic venous thromboembolism during 3-month follow-up. This included fatal pulmonary embolism, nonfatal pulmonary embolism, and DVT. An independent adjudication committee, unaware of the patients result of the clinical decision rule, evaluated all suspected venous thromboembolic events and deaths. A diagnosis of pulmonary embolism or DVT was based on a prioridefined and generally accepted criteria (Appendix Table) (17). Deaths were classified as caused by pulmonary embolism when autopsy was done if an objective test result was positive for pulmonary embolism before death or if pulmonary embolism could not be confidently excluded as the cause of death (17). Appendix Table. Adjudication Criteria Used for the AMUSE Study Statistical Analysis On the basis of an expected incidence of venous thromboembolism in 1% of patients (those with a score 3) during 3-month follow-up and the exclusion of a predetermined incidence of 4% or more, we calculated that 488 patients needed to be included in this low-risk group (type I error, 0.05; type II error, 0.2). The primary analysis was about the incidence (with exact 95% CI) of symptomatic venous thromboembolism during 3-month follow-up in the group of patients with a score of 3 or less who were not referred for further testing or treatment. In addition, we calculated the percentage of patients with a score of 3 or less. Furthermore, we calculated the probability of venous thromboembolism on leg ultrasonography at baseline or during follow-up, according to the results of the clinical decision rule without the d-dimer assay result, as well as the d-dimer assay result alone. For this purpose, a cutoff of 3 or less was also used because on the basis of this cutoff, patients with a negative d-dimer result should still receive a referral for ultrasonography. Role of the Funding Source The study was funded by the Netherlands Organization for Scientific Research. The funding source had no role in the design, conduct, or reporting of the study or in the decision to submit the manuscript for publication. Results Patients We assessed 1086 consecutive patients with clinically suspected DVT. We excluded 58 patients (5.3%) because of predefined exclusion criteria (Figure). Table 2 shows characteristics of the 1028 study patients, including the items of the clinical decision rule. The mean age was 58 years, and 37% were men. Suspicion of DVT that led to study inclusion was based most commonly on leg pain (87%) and leg swelling (78%). Figure. Study flow diagram. CDR = clinical decision rule; DVT = deep venous thrombosis; DVT+ = deep venous thrombosis confirmed by ultrasonography; DVT = deep venous thrombosis excluded by ultrasonography; LMWH = low-molecular-weight heparin; PE = pulmonary embolism; VTE = venous thromboembolism. * All patients were referred for ultrasonography on the day of presentation. No clinical events occurred in this group. Clearview Simplify d-dimer assay, Inverness Medical, Bedford, United Kingdom. Incidence of VTE, 1.4% (95% CI, 0.6% to 2.9%). If the 1 patient lost to follow-up had developed VTE, the percentage missed by the procedure would have been 1.6% instead of 1.4%. Table 2. Demographic and Clinical Characteristics of the Study Sample (n= 1028) Results of the Clinical Decision Rule In 500 of 1028 patients (49%), the score was 3 or les

Individually tailored duration of elastic compression therapy in relation to incidence of the postthrombotic syndrome

OBJECTIVE We assessed whether individualized shortened duration of elastic compression stocking (ECS) therapy after acute deep venous thrombosis (DVT) is feasible without increasing the incidence of postthrombotic syndrome (PTS). METHODS At the outpatient clinic of the Maastricht University Medical Centre, 125 consecutive patients with confirmed proximal DVT were followed for 2 years. Villalta scores were assessed on four consecutive visits; 3, 6, 12, and 24 months after the acute event. Reflux was assessed once by duplex testing. After 6 months, patients with scores <or=4 on the Villalta clinical score and in the absence of reflux were allowed to discontinue ECS therapy. If reflux was present, two consecutive scores <or=4 were needed to discontinue ECS therapy. RESULTS ECS therapy was discontinued in 17% of patients at 6 months, in 48% at 12 months, and in 50% at 24 months. Reflux on duplex testing was present in 74/101 (73.3%) tested patients and was not associated with the onset of PTS. At the 6-month visit, the cumulative incidence of PTS was 13.3%, at 12 months 17.0%, and at 24 months 21.1%. Varicosities/venous insufficiency (present at baseline) was significantly associated with PTS; hazard ratio 3.2 (1.2-9.1). CONCLUSIONS Patients with a low probability for developing PTS can be identified as early as 6 months after the thrombotic event, and individualized shortened duration of ECS therapy based on Villalta clinical scores may be a safe management option. These findings need to be confirmed in a randomized clinical trial.

Diagnostic value of immunoassays for heparin-induced thrombocytopenia: a systematic review and meta-analysis

Immunoassays are essential in the workup of patients with suspected heparin-induced thrombocytopenia. However, the diagnostic accuracy is uncertain with regard to different classes of assays, antibody specificities, thresholds, test variations, and manufacturers. We aimed to assess diagnostic accuracy measures of available immunoassays and to explore sources of heterogeneity. We performed comprehensive literature searches and applied strict inclusion criteria. Finally, 49 publications comprising 128 test evaluations in 15 199 patients were included in the analysis. Methodological quality according to the revised tool for quality assessment of diagnostic accuracy studies was moderate. Diagnostic accuracy measures were calculated with the unified model (comprising a bivariate random-effects model and a hierarchical summary receiver operating characteristics model). Important differences were observed between classes of immunoassays, type of antibody specificity, thresholds, application of confirmation step, and manufacturers. Combination of high sensitivity (>95%) and high specificity (>90%) was found in 5 tests only: polyspecific enzyme-linked immunosorbent assay (ELISA) with intermediate threshold (Genetic Testing Institute, Asserachrom), particle gel immunoassay, lateral flow immunoassay, polyspecific chemiluminescent immunoassay (CLIA) with a high threshold, and immunoglobulin G (IgG)-specific CLIA with low threshold. Borderline results (sensitivity, 99.6%; specificity, 89.9%) were observed for IgG-specific Genetic Testing Institute-ELISA with low threshold. Diagnostic accuracy appears to be inadequate in tests with high thresholds (ELISA; IgG-specific CLIA), combination of IgG specificity and intermediate thresholds (ELISA, CLIA), high-dose heparin confirmation step (ELISA), and particle immunofiltration assay. When making treatment decisions, clinicians should be a aware of diagnostic characteristics of the tests used and it is recommended they estimate posttest probabilities according to likelihood ratios as well as pretest probabilities using clinical scoring tools.

Management of deep vein thrombosis and prevention of post-thrombotic syndrome.

#### Summary points The annual global incidence of deep vein thrombosis (DVT) of the leg is 1.6 per 1000.1 Classically, venous thrombosis of a lower limb begins in a deep calf vein and propagates more proximally. Symptoms include swelling, pain, and redness of the leg, depending on the vein segment(s) involved (see table 1⇓).2 Patients are at risk of pulmonary embolism.3 Despite optimal conservative treatment with anticoagulation and compression, one in four patients develops a post-thrombotic syndrome within one year,2 and one in three develops a recurrent DVT within five years.4 Patients with post-thrombotic syndrome have poor quality of life.5 A more aggressive approach to treatment, such as removal of early thrombus using catheter directed thrombolysis, might improve outcomes for patients with DVT compared with standard anticoagulation treatment.4 5 6 7 8 9 10 11 12 We review standard and new, more aggressive, management of DVT for the generalist reader, drawing from recent guidelines, cohort studies, small randomised controlled trails, and meta-analyses. All authors are investigators in the CAVA trial, which is one of three randomised controlled trials currently investigating outcomes after treatment with catheter …

The IDEAL DVT study, individualised duration elastic compression therapy against long-term duration of therapy for the prevention of post-thrombotic syndrome: protocol of a randomised controlled trial

Introduction Post-thrombotic syndrome (PTS) is a serious complication of deep vein thrombosis (DVT) of the leg that affects 20–50% of patients. Once a patient experiences PTS there is no treatment that effectively reduces the debilitating complaints. Two randomised controlled trials showed that elastic compression stocking (ECS) therapy after DVT for 24 months can reduce the incidence of PTS by 50%. However, it is unclear whether all patients benefit to the same extent from ECS therapy or what the optimal duration of therapy for individual patients should be. ECS therapy is costly, inconvenient, demanding and sometimes even debilitating. Tailoring therapy to individual needs could save substantial costs. The objective of the IDEAL DVT study, therefore, is to evaluate whether tailoring the duration of ECS therapy on signs and symptoms of the individual patient is a safe and effective method to prevent PTS, compared with standard ECS therapy. Methods and analysis A multicentre, single-blinded, allocation concealed, randomised, non-inferiority trial. A total of 864 consecutive patients with acute objectively documented proximal DVT of the leg are randomised to either standard duration of 24 months or tailored duration of ECS therapy following an initial therapeutic period of 6 months. Signs and symptoms of PTS are recorded at regular clinic visits. Furthermore, quality of life, costs, patient preferences and compliance are measured. The primary outcome is the proportion of patients with PTS at 24 months. Ethics and dissemination Based on current knowledge the standard application of ECS therapy is questioned. The IDEAL DVT study will address the central questions that remain unanswered: Which individual patients benefit from ECS therapy and what is the optimal individual treatment duration? Primary ethics approval was received from the Maastricht University Medical Centre. Results Results of the study will be disseminated via peer-reviewed publications and presentations at scientific conferences. Trial registration number NCT01429714 and NTR 2597.

Screen or not to screen for peripheral arterial disease: guidance from a decision model

BackgroundAsymptomatic Peripheral Arterial Disease (PAD) is associated with greater risk of acute cardiovascular events. This study aims to determine the cost-effectiveness of one time only PAD screening using Ankle Brachial Index (ABI) test and subsequent anti platelet preventive treatment (low dose aspirin or clopidogrel) in individuals at high risk for acute cardiovascular events compared to no screening and no treatment using decision analytic modelling.MethodsA probabilistic Markov model was developed to evaluate the life time cost-effectiveness of the strategy of selective PAD screening and consequent preventive treatment compared to no screening and no preventive treatment. The analysis was conducted from the Dutch societal perspective and to address decision uncertainty, probabilistic sensitivity analysis was performed. Results were based on average values of 1000 Monte Carlo simulations and using discount rates of 1.5% and 4% for effects and costs respectively. One way sensitivity analyses were performed to identify the two most influential model parameters affecting model outputs. Then, a two way sensitivity analysis was conducted for combinations of values tested for these two most influential parameters.ResultsFor the PAD screening strategy, life years and quality adjusted life years gained were 21.79 and 15.66 respectively at a lifetime cost of 26,548 Euros. Compared to no screening and treatment (20.69 life years, 15.58 Quality Adjusted Life Years, 28,052 Euros), these results indicate that PAD screening and treatment is a dominant strategy. The cost effectiveness acceptability curves show 88% probability of PAD screening being cost effective at the Willingness To Pay (WTP) threshold of 40000 Euros. In a scenario analysis using clopidogrel as an alternative anti-platelet drug, PAD screening strategy remained dominant.ConclusionThis decision analysis suggests that targeted ABI screening and consequent secondary prevention of cardiovascular events using low dose aspirin or clopidogrel in the identified patients is a cost-effective strategy. Implementation of targeted PAD screening and subsequent treatment in primary care practices and in public health programs is likely to improve the societal health and to save health care costs by reducing catastrophic cardiovascular events.

Determinants of agreement between proposed therapeutic windows of platelet function tests in vulnerable patients.

Aims Therapeutic windows for residual platelet reactivity in patients with coronary artery disease on P2Y12 inhibitors were proposed in a consensus document. We aimed to explore the level of agreement between windows for different platelet function tests (PFTs) used to classify patients in low, optimal, and high on-treatment platelet reactivity categories, and to identify variables contributing to the level of agreement. Methods and results In this explorative clinical study, the VerifyNow P2Y12, Multiplate adenosine diphosphate (ADP), and light transmission aggregometry (LTA) 20 &mgr;mol/L ADP were performed simultaneously in 145 consecutive vulnerable patients. Measurements were performed within 6 months of percutaneous intervention. Patients were considered vulnerable if they had ≥2 risk factors for bleeding or ischaemic events. Window-agreement between PFT pairs was slight to moderate. Multiplate–VerifyNow agreed in 72 patients (50%), &kgr; = 0.41; VerifyNow–LTA agreed in 76 patients (52%), &kgr; = 0.36; and LTA–Multiplate agreed in 64 patients (44%), &kgr; = 0.20. Several variables including the type of P2Y12 inhibitor, aspirin, haemoglobin level, platelet count, age, and previous stroke significantly influenced agreement between PFTs. Conclusions Our results suggest that the PFTs, with accompanying therapeutic windows, are not interchangeable when determining the response to antiplatelet therapy in vulnerable coronary artery disease patients on P2Y12 inhibitors. Hence, the type of PFT can directly affect the treatment strategy, which may be especially relevant for patients with multiple factors influencing individual PFTs and thereby test agreement.

The cost–effectiveness of point-of-care D-dimer tests compared with a laboratory test to rule out deep venous thrombosis in primary care

Objective: Point-of-care (POC) D-dimer tests have been developed to exclude deep venous thrombosis quickly and on the spot, but are known to have lower sensitivity compared with laboratory-based tests. Their cost–effectiveness is still unknown. Methods: We updated and extended a previously published Markov model to assess the cost–effectiveness of POC D-dimer tests (‘Simplify’, ‘Cardiac’, ‘Triage’ and ‘Nycocard’) compared with a laboratory-based latex assay to diagnose deep venous thrombosis in primary care. Results: The ‘Laboratory’ strategy resulted in 6.986 quality-adjusted life years at the cost of €8354 per patient. All POC D-dimer tests resulted in health outcomes similar to the ‘Laboratory’ strategy. The ‘Simplify’ strategy maximized cost savings (–€155 [95% CI: –€246 to –€83]). Conclusions: POC D-dimer tests yield similar health outcomes as laboratory-based testing procedures but can be performed more easily and at lower costs. Therefore, these tests are an alternative to laboratory-based testing and might be considered for exclusion of deep venous thrombosis in primary care.

Platelet dysfunction in thrombosis patients treated with vitamin K antagonists and recurrent bleeding.

Background Recurrent bleeding can complicate the treatment of thrombosis patients with vitamin K antagonists (VKA), even at a well-regulated level of anticoagulation. In this proof-of-principle study, we investigated whether alterations in platelet function or von Willebrand factor (vWf) contribute to a bleeding phenotype in these patients. Methods In this case-control study 33 well-regulated patients without bleeding events (controls) and 33 patients with recurrent bleeding (cases) were retrospectively included. Thrombin generation and vWf were determined in plasma. Platelet function was assessed by light transmission aggregometry and flow cytometry using a validated panel of agonists. Results Thrombin generation was similarly reduced in controls and cases, in comparison to normal plasma. Plasma vWf level was above the normal range in 85% of controls and 67% of the cases. vWf activity was similarly increased in all patients in comparison to healthy volunteers. Platelet aggregation was in the normal range for almost all patients irrespective of the type of agonist. However, in response to a low collagen dose, platelets from 21% of controls and 27% of cases showed diminished responses. Agonist-induced secretion of alpha- and dense-granules or integrin αIIbβ3 activation were affected in platelets from neither controls nor cases. Conclusion Recurrent bleeding in well-controlled patients on VKA therapy is not explained by anti-hemostatic changes in platelet or vWf function.

Appropriate level and length of postthrombotic warfarin treatment: an evaluation of recent developments.

AbstractCurrent treatment and secondary prophylaxis of venous thromboembolism has two major drawbacks. During vitamin K antagonist therapy, patients need to be monitored closely to maintain efficacy and minimize the bleeding risk due to fluctuations of the prothrombin time (international normalized ratio, INR), and after cessation of therapy there is the problem of recurrent thrombosis, ie, the catch-up phenomenon. Recent studies indicate that for most patients, vitamin K antagonist therapy aimed at an INR of 2.0 to 3.0 is optimal. For patients with thrombosis due to a temporary risk factor, extending treatment beyond 3 months is not needed, whereas for other patients a minimal duration of 1 year can be advocated. For patients with cancer, it is beneficial to postpone therapy with vitamin K antagonists and prolong initial low-molecular-weight therapy for 3 to 6 months. New developments are aimed at further individualization of the duration of treatment and at the introduction of agents that are suitable for long-term treatment and do not require monitoring.