Ruling out pulmonary embolism across different subgroups of patients and healthcare settings: protocol for a systematic review and individual patient data meta-analysis (IPDMA).

BACKGROUND: Diagnosing pulmonary embolism in suspected patients is notoriously difficult as signs and symptoms are non-specific. Different diagnostic strategies have been developed, usually combining clinical probability assessment with D-dimer testing. However, their predictive performance differs across different healthcare settings, patient subgroups, and clinical presentation, which are currently not accounted for in the available diagnostic approaches. METHODS: This is a protocol for a large diagnostic individual patient data meta-analysis (IPDMA) of currently available diagnostic studies in the field of pulmonary embolism. We searched MEDLINE (search date January 1, 1995, till August 25, 2016) to retrieve all primary diagnostic studies that had evaluated diagnostic strategies for pulmonary embolism. Two authors independently screened titles, abstracts, and subsequently full-text articles for eligibility from 3145 individual studies. A total of 40 studies were deemed eligible for inclusion into our IPDMA set, and principal investigators from these studies were invited to participate in a meeting at the 2017 conference from the International Society on Thrombosis and Haemostasis. All authors agreed on data sharing and participation into this project. The process of data collection of available datasets as well as potential identification of additional new datasets based upon personal contacts and an updated search will be finalized early 2018. The aim is to evaluate diagnostic strategies across three research domains: (i) the optimal diagnostic approach for different healthcare settings, (ii) influence of comorbidity on the predictive performance of each diagnostic strategy, and (iii) optimize and tailor the efficiency and safety of ruling out PE across a broad spectrum of patients with a new, patient-tailored clinical decision model that combines clinical items with quantitative D-dimer testing. DISCUSSION: This pre-planned individual patient data meta-analysis aims to contribute in resolving remaining diagnostic challenges of time-efficient diagnosis of pulmonary embolism by tailoring available diagnostic strategies for different healthcare settings and comorbidity. SYSTEMATIC REVIEW REGISTRATION: Prospero trial registration: ID 89366.

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.

D-dimer levels and recurrence in patients with unprovoked VTE and a negative qualitative D-dimer test after treatment.

BACKGROUND: The rate of recurrent venous thromboembolism (VTE) in patients with a first unprovoked VTE who had a negative qualitative D-dimer test one month after stopping anticoagulant therapy was higher than expected in the D-dimer Optimal Duration Study (DODS). OBJECTIVES: To determine whether quantitative D-dimer levels using a low threshold, age- and sex-specific thresholds, or repeated measurements, would improve identification of patients at low risk of recurrent VTE. MATERIALS AND METHODS: D-dimer levels were quantified in banked samples from 307 patients in DODS who had a negative qualitative D-dimer test while on, and 1month after stopping, anticoagulant therapy and the rates of recurrent VTE were determined in patients with D-dimer levels below various predefined thresholds. RESULTS: The rate (per patient year) of recurrent VTE was: 5.9% with D-dimer levels<250µg/l at one month; 5.2% with D-dimer levels between 250 and 499µg/l at one month; 5.0% with D-dimer levels less than predefined age- and sex-specific thresholds at one month; and 6.3% when D-dimer levels were <500µg/l at both one and 7months after stopping anticoagulant therapy. These rates are similar to the overall event rate of 6.3% in patients who stopped treatment. CONCLUSIONS: Among unprovoked VTE patients who had a negative qualitative D-dimer test during and after anticoagulant therapy, low D-dimer thresholds, age and sex-adjusted thresholds or repeated measurements, did not identify subgroups with a very low rate of recurrence.

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.

Is it useful to also image the asymptomatic leg in patients with suspected deep vein thrombosis?

BACKGROUND: Venous ultrasonography is the cornerstone of the diagnostic work-up in patients with suspected deep vein thrombosis (DVT). Significant variations exist in clinical practice between centers and/or countries, e.g. proximal vs. whole-leg ultrasound, serial tests vs. single test, and combination with clinical probability and D-dimer testing. Fewer data exist on the need for bilateral leg imaging. OBJECTIVES: To assess the yield of bilateral leg ultrasonography in patients with suspected DVT. PATIENTS AND METHODS: This was a retrospective cohort study of consecutive patients with clinically suspected DVT. A single whole-leg ultrasound scan was performed in all patients. We extracted information on demographics, risk factors, clinical signs, pretest probability, side of clinical suspicion, and ultrasound results. RESULTS AND CONCLUSIONS: Among the 2804 included patients, 609 (21.8%) patients had a positive ultrasound finding. A total of 20 patients (0.8%; 95% confidence interval [CI] 0.5-1.2%) had a thrombus diagnosed in both the symptomatic leg and asymptomatic leg. Moreover, five patients (0.2%; 95% CI 0.1-0.5%) did not have a thrombus in the symptomatic leg but had a thrombus in the asymptomatic leg. Two of 2540 patients with unilateral symptoms had no proximal DVT in the symptomatic leg and a proximal DVT in the asymptomatic leg (0.08%; 95% CI 0.0-0.3%). In summary, systematic imaging of both legs in patients with suspected DVT has a very low yield, and therefore does not appear to be justified.

Inflammation markers and their trajectories after deep vein thrombosis in relation to risk of post-thrombotic syndrome.

BACKGROUND: Post-thrombotic syndrome (PTS) is a frequent chronic complication of deep vein thrombosis (DVT). OBJECTIVE: In the BioSOX study, we investigated whether inflammation markers predict the risk of PTS after DVT. METHODS: We measured C-reactive protein (CRP), ICAM-1, interleukin (IL)-6, and IL-10, at baseline, and 1 month and 6 months after a first proximal DVT, among 803 participants in the SOX trial. Participants were prospectively followed for 24 months for development of PTS. RESULTS: Median CRP levels at 1 month, ICAM-1 levels at baseline, 1 month and 6 months, IL-6 levels at 1 month and 6 months and IL-10 levels at 6 months were higher in patients who developed PTS than in those who did not. Multivariable regression with the median as a cutoff showed risk ratios (RRs) for PTS of 1.23 (95% confidence interval [CI] 1.05-1.45) and 1.25 (95% CI 1.05-1.48) for ICAM-1 at 1 month and 6 months, respectively, and 1.27 (95% CI 1.07-1.51) for IL-10 at 6 months. Quartile-based analysis demonstrated a dose-response association between ICAM-1 and PTS. ICAM-1 and IL-10 were also associated with PTS severity. Analysis of biomarker trajectories after DVT demonstrated an association between the highest-trajectory group of ICAM-1 and PTS. CONCLUSIONS: In this prospective study, ICAM-1 over time was most consistently associated with the risk of PTS. Further study is required to confirm these findings and assess their potential clinical relevance.

Graduated compression stockings to treat acute leg pain associated with proximal DVT. A randomised controlled trial.

Acute deep venous thrombosis (DVT) causes leg pain. Elastic compression stockings (ECS) have potential to relieve DVT-related leg pain by diminishing the diameter of distended veins and increasing venous blood flow. It was our objective to determine whether ECS reduce leg pain in patients with acute DVT. We performed a secondary analysis of the SOX Trial, a multicentre randomised placebo controlled trial of active ECS versus placebo ECS to prevent the post-thrombotic syndrome.The study was performed in 24 hospital centres in Canada and the U.S. and included 803 patients with a first episode of acute proximal DVT. Patients were randomised to receive active ECS (knee length, 30-40 mm Hg graduated pressure) or placebo ECS (manufactured to look identical to active ECS, but lacking therapeutic compression). Study outcome was leg pain severity assessed on an 11-point numerical pain rating scale (0, no pain; 10, worst possible pain) at baseline, 14, 30 and 60 days after randomisation. Mean age was 55 years and 60% were male. In active ECS patients (n=409), mean (SD) pain severity at baseline and at 60 days were 5.18 (3.29) and 1.39 (2.19), respectively, and in placebo ECS patients (n=394) were 5.38 (3.29) and 1.13 (1.86), respectively. There were no significant differences in pain scores between groups at any assessment point, and no evidence for subgroup interaction by age, sex or anatomical extent of DVT. Results were similar in an analysis restricted to patients who reported wearing stockings every day. In conclusion, ECS do not reduce leg pain in patients with acute proximal DVT.

Influence of sex on risk of bleeding in anticoagulated patients: a systematic review and meta-analysis.

BACKGROUND: The risk of bleeding on anticoagulation varies between patients. It is uncertain whether sex influences this risk. OBJECTIVES: To determine if the risk of major bleeding differs between men and women receiving anticoagulation for atrial fibrillation or venous thromboembolism(VTE). METHODS: We searched MEDLINE, EMBASE, and Cochrane databases, and relevant conference proceedings, until February 2013. We included randomized controlled trials and prospective cohort studies of patients on therapeutic anticoagulation for atrial fibrillation or VTE. Two reviewers independently extracted data. The relative risk of bleeding in men compared to women was pooled using a random-effects model. RESULTS: Forty-two studies including 94 293 patients were eligible; 78 044 patients (83%) had atrial fibrillation; 16 156 patients (17%) had VTE; 37 250 patients were women (40%); and there were 4147 major bleeds. The relative risk of major bleeding for men vs. women was 1.02(95% CI 0.95­1.10; P = 0.27 for heterogeniety). The relative risk was 1.02 (95% CI 0.95­1.09) in patients with atrial fibrillation and 0.80 (95% CI 0.65­0.98) in patients with VTE (P = 0.03 for subgroup effect). Type of anticoagulant,intensity of anticoagulation, and whether patients began or were already established on anticoagulants at enrollment did not influence the relative risk of major bleeding in men compared to women. CONCLUSIONS: The risk of major bleeding on anticoagulation appears to be the same in men and women, particularly if patients have atrial fibrillation. This finding is less certain for patients with VTE, in whom the risk of bleeding may be marginally lower in men compared to in women.

Meta-analysis of randomized trials comparing combined compression and anticoagulation with either modality alone for prevention of venous thromboembolism after surgery.

BACKGROUND: Although venous thromboembolism (VTE) is an important cause of postoperative morbidity and mortality, there is still no consensus on the optimal strategy for VTE prevention after major surgery. The objective of this review was to determine the benefits and risks of thromboprophylaxis with both compression and anticoagulation, compared with either modality alone. METHODS: A systematic review of MEDLINE, CENTRAL and Embase databases was performed to identify eligible randomized trials. The literature search and data extraction were carried out independently by two reviewers. Outcomes of interest were deep vein thrombosis (DVT), pulmonary embolism, bleeding, limb injury and mortality. RESULTS: Twenty-five studies were eligible for inclusion. Adding compression to anticoagulation decreased the risk of DVT by 49 per cent (risk ratio (RR) 0·51, 95 per cent confidence interval 0·36 to 0·73). The corresponding funnel plot suggested publication bias and, overall, the evidence for this comparison was judged to be of low quality. Adding anticoagulation to compression decreased the risk of DVT by 44 per cent (RR 0·56, 0·45 to 0·69) while increasing the risk of bleeding (RR 1·74, 1·29 to 2·34). There was no suggestion of publication bias and the evidence for this comparison was judged to be of moderate quality. CONCLUSION: Combined compression and anticoagulation is more effective at preventing postoperative DVT than either modality alone. However, adding anticoagulation to compression increases the risk of bleeding, and the evidence that adding compression to anticoagulation reduces VTE risk is of low quality.

Loading dose vs. maintenance dose of warfarin for reinitiation after invasive procedures: a randomized trial.

BACKGROUND: There is uncertainty regarding the optimal dosing regimen for the resumption of warfarin after interruption for invasive procedures. AIM: To determine the efficacy and safety of warfarin resumption with loading doses or with the most recent maintenance dose. METHODS: Patients receiving warfarin treatment and planned for invasive procedures with an expected hospital stay of ≤ 1 day were randomized to resume warfarin on the day of the procedure, defined as day 1, with most recent maintenance dose or with 2 initial days of double maintenance dose. Efficacy outcomes were proportion of international normalized ratio (INR) levels ≥ 2.0 on day 5 (primary outcome) and day 10. Safety outcomes were bleeding and thromboembolic events. In addition, D-dimer levels were analyzed on days 5 and 10 in a subset of the population. RESULTS: There were 49 patients analyzed in each group. INR of ≥ 2.0 had been achieved by day 5 for 13% in the maintenance-dose group and for 50% in the loading-dose group (relative risk [RR] 0.27, 95% confidence interval [CI] 0.10-0.60) and by day 10 for 68% and 87%, respectively (RR 0.78, 95% CI 0.65-1.00). There were no thromboembolic events, and there was one major bleed before resumption of warfarin and one minor bleed, both in the maintenance-dose group. There was no difference between the groups in the proportion of patients with excessive INRs or elevated D-dimer levels or in the median D-dimer level. CONCLUSION: Resumption of warfarin after minor-moderately invasive procedures with two loading doses achieves therapeutic INR faster than does only maintenance dose.

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.

A conceptual framework for two phases of anticoagulant treatment of venous thromboembolism.

Four observations support that anticoagulant therapy for venous thromboembolism (VTE) has an 'active treatment' phase that is limited to about 3 months. First, <3 months of treatment is associated with a higher risk of recurrent VTE than treatment for 3 months or longer, suggesting that <3 months is inadequate therapy. Second, treatment for 3 months is associated with the same risk of recurrent VTE as treatment for 6 months or longer, suggesting that 3 months is adequate therapy. Third, the increase in recurrent VTE with too short a course of treatment is predominantly at the site of the initial thrombosis, suggesting reactivation of initial thrombosis. Fourth, the increase in recurrent VTE with too short a course of treatment occurs immediately after treatment is stopped and is short lived, again suggesting reactivation of initial thrombosis. Once the initial thrombosis has been adequately treated (i.e. the first phase of treatment), further anticoagulation serves as 'secondary prevention' of new, unrelated, episodes of thrombosis (i.e. the second phase of treatment). For most patients, therefore, anticoagulant therapy for VTE should be stopped at 3 months when the acute episode has completed treatment, or should be continued indefinitely as 'secondary prevention' if the risk of recurrence remains unacceptably high having completed 'active treatment'.

Diagnosis of DVT: antithrombotic therapy and prevention of thrombosis: American College of Chest Physicians evidence-based clinical practice guidelines

BACKGROUND: Objective testing for DVT is crucial because clinical assessment alone is unreliable and the consequences of misdiagnosis are serious. This guideline focuses on the identification of optimal strategies for the diagnosis of DVT in ambulatory adults. METHODS: The methods of this guideline follow those described in Methodology for the Development of Antithrombotic Therapy and Prevention of Thrombosis Guidelines: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. RESULTS: We suggest that clinical assessment of pretest probability of DVT, rather than performing the same tests in all patients, should guide the diagnostic process for a first lower extremity DVT (Grade 2B). In patients with a low pretest probability of first lower extremity DVT, we recommend initial testing with D-dimer or ultrasound (US) of the proximal veins over no diagnostic testing (Grade 1B), venography (Grade 1B), or whole-leg US (Grade 2B). In patients with moderate pretest probability, we recommend initial testing with a highly sensitive D-dimer, proximal compression US, or whole-leg US rather than no testing (Grade 1B) or venography (Grade 1B). In patients with a high pretest probability, we recommend proximal compression or whole-leg US over no testing (Grade 1B) or venography (Grade 1B). CONCLUSIONS: Favored strategies for diagnosis of first DVT combine use of pretest probability assessment, D-dimer, and US. There is lower-quality evidence available to guide diagnosis of recurrent DVT, upper extremity DVT, and DVT during pregnancy.

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.