Idarucizumab for dabigatran reversal: A systematic review and meta-analysis of indications and outcomes.

BACKGROUND: Idarucizumab has been approved to reverse the anticoagulant effect of dabigatran. However, there is little knowledge of the effectiveness and safety of idarucizumab in daily practice. AIMS: This systematic review and meta-analysis aims to evaluate the use, effectiveness and outcomes of idarucizumab. METHODS: A systematic literature search was performed up to September 8th 2022. Original studies including patients prescribed idarucizumab, evaluating prescription indications, prescription appropriateness, haemostatic efficacy and/or the occurrence of adverse events were eligible. Case-reports and studies performed in patients ≤18 years or in healthy volunteers were excluded. Study selection and data extraction were performed by two independent reviewers. Pooled estimates were calculated using the random-effects model, after Freeman-Tukey double-arcsine transformation. RESULTS: Thirty studies comprising 3602 patients were included. Idarucizumab was prescribed for bleeding (63.1 %, 95%CI 57.0 %-69.0 %), invasive procedures (30.5 %, 95%CI: 24.1 %-37.2 %), to enable thrombolysis (range: 2.0 %-27.3 %), dabigatran intoxication without bleeding (range: 3.6 %-7.0 %) or unspecified reasons (range: 0.4 %-18.8 %). Overall, 2.8 % (95%CI 0.5 %-6.2 %) of prescription indications were reported to be inappropriate upon post-hoc evaluation. Hemostatic effectiveness was achieved in 77.7 % (95%CI 66.7 %-87.2 %) and peri-procedural haemostasis was normal in 98.5 % (95%CI 86.6 %-100 %) of patients. The pooled incidences of all-cause mortality and thromboembolic events at any follow-up duration were 13.6 % (95%CI 9.6 %-17.9 %) and 2.0 % (95%CI 0.8 %-3.4 %), respectively. CONCLUSION: Idarucizumab was mainly prescribed in the setting of bleeding. The reported hemostatic effectiveness was good, especially perioperatively, and the incidence of thromboembolic events was low. Patients with dabigatran-associated bleeding or requiring an urgent procedure nonetheless face a high mortality risk.

The YEARS algorithm for suspected pulmonary embolism: shorter visit time and reduced costs at the emergency department.

Essentials The YEARS algorithm was designed to simplify the diagnostic workup of suspected pulmonary embolism. We compared emergency ward turnaround time of YEARS and the conventional algorithm. YEARS was associated with a significantly shorter emergency department visit time of ˜60 minutes. Treatment of pulmonary embolism was initiated 53 minutes earlier with the YEARS algorithm SUMMARY: Background Recently, the safety of the YEARS algorithm, designed to simplify the diagnostic work-up of pulmonary embolism (PE), was demonstrated. We hypothesize that by design, YEARS would be associated with a shorter diagnostic emergency department (ED) visit time due to simultaneous assessment of pre-test probability and D-dimer level and reduction in number of CT scans. Aim To investigate whether implementation of the YEARS diagnostic algorithm is associated with a shorter ED visit time compared with the conventional algorithm and to evaluate the associated cost savings. Methods We selected consecutive outpatients with suspected PE from our hospital included in the YEARS study and ADJUST-PE study. Different time-points of the diagnostic process were extracted from the to-the-minute accurate electronic patients' chart system of the ED. Further, the costs of the ED visits were estimated for both algorithms. Results All predefined diagnostic turnaround times were significantly shorter after implementation of YEARS: patients were discharged earlier from the ED; 54 min (95% CI, 37-70) for patients managed without computed tomography pulmonary angiography (CTPA) and 60 min (95% CI, 44-76) for the complete study population. Importantly, patients diagnosed with PE by CTPA received the first dose of anticoagulants 53 min (95% CI, 22-82) faster than those managed according to the conventional algorithm. Total costs were reduced by on average €123 per visit. Conclusion YEARS was shown to be associated with a shorter ED visit time compared with the conventional diagnostic algorithm, leading to faster start of treatment in the case of confirmed PE and savings on ED resources.

Performance of the age-adjusted cut-off for D-dimer in patients with cancer and suspected pulmonary embolism.

BACKGROUND: Cancer patients frequently present with suspected pulmonary embolism (PE). The D-dimer (DD) test is less useful in excluding PE in cancer patients due to the lower specificity. In the general population, the age-adjusted cutoff for DD combined with a clinical decision rule (CDR) improved specificity in the diagnosis of PE. OBJECTIVES: To evaluate the safety and efficacy of the age-adjusted cutoff (defined as age∗10µg/L in patients >50years) combined with a CDR for the exclusion of PE in cancer patients. METHODS: We conducted a prospective study to evaluate the age-adjusted cutoff in patients with suspected PE. Here we report a post-hoc analysis on the performance of the age-adjusted cutoff in patients with and without cancer. The primary outcome was the rate of venous thromboembolic events (VTE) during three-month follow-up. RESULTS: Of 3324 patients with suspected PE, 429 (12.9%) patients had cancer. The prevalence of PE was 25.2% in cancer patients and 18% in patients without cancer (p<0.001). Among cancer patients with an unlikely CDR, 9.9% had a DD <500µg/L as compared with 19.7% using the age-adjusted cutoff. In patients without cancer, these rates were 30.1% and 41.9%. The proportion of cancer patients in whom PE could be excluded by CDR and DD doubled from 6.3% to 12.6%. No VTE occurred during three-month follow-up (failure rate 0.0% (95% CI 0.0-6.9%)). CONCLUSION: Compared with the conventional cutoff, the age-adjusted D-dimer cutoff doubles the proportion of patients with cancer in whom PE can be safely excluded by CDR and DD without imaging.

The original and simplified Wells rules and age-adjusted D-dimer testing to rule out pulmonary embolism: an individual patient data meta-analysis.

Essentials Evidence for the simplified Wells rule in ruling out acute pulmonary embolism (PE) is scarce. This was a post-hoc analysis on data from 6 studies comprising 7268 patients with suspected PE. The simplified Wells rule combined with age-adjusted D-dimer testing may safely rule out PE. Given its ease of use, the simplified Wells rule is to be preferred over the original Wells rule. SUMMARY: Background The Wells score and D-dimer testing can safely rule out pulmonary embolism (PE). A simplification of the Wells score has been proposed to improve clinical applicability, but evidence on its performance is scarce. Objectives To compare the performances of the original and simplified Wells scores alone and in combination with age-adjusted D-dimer testing. Methods Individual patient data from 7268 patients with suspected PE enrolled in six management studies were used to evaluate the discriminatory performances of the original and simplified Wells scores. The efficiency and failure rate of the dichotomized original and simplified scores combined with age-adjusted D-dimer testing were compared by use of a one-stage random effects meta-analysis. Efficiency was defined as the proportion of patients in whom PE could be considered to be excluded on the basis of a 'PE unlikely' Wells score and a negative age-adjusted D-dimer test result. Failure rate was defined as the proportion of patients with symptomatic venous thromboembolism during a 3-month follow-up. Results The discriminatory performances of the original and simplified Wells scores were comparable (c-statistic 0.73 [95% confidence interval (CI) 0.72-0.75] versus 0.72 [95% CI 0.70-0.73]). When combined with age-adjusted D-dimer testing, the original and simplified Wells rules had comparable efficiency (3% [95% CI 25-42%] versus 30% [95% CI 21-40%]) and failure rates (0.9% [95% CI 0.6-1.5%] versus 0.8% [95% CI 0.5-1.3%]). Conclusion The original and simplified Wells rules combined with age-adjusted D-dimer testing have similar performances in ruling out PE. Given its ease of use in clinical practice, the simplified Wells rule is to be preferred.

Continuation of low-molecular-weight heparin treatment for cancer-related venous thromboembolism: a prospective cohort study in daily clinical practice.

Essentials Low-molecular-weight heparin (LMWH) injections for venous thromboembolism (VTE) may be burdensome. Patients with active cancer and confirmed VTE were included to evaluate LMWH continuation. The cumulative incidence of discontinuation was 21% after a median period of 90 days. One out of five patients discontinued LMWH injections because of side effects. SUMMARY: Background Current guidelines recommend low-molecular-weight heparin (LMWH) monotherapy for 3-6 months as the first-line treatment for cancer-associated venous thromboembolism (VTE). However, although daily administration of LMWH injections over a course of several months may be burdensome, the number of patients who stop treatment because of LMWH side-effects is unknown. Objectives To evaluate the continuation rate and complications of daily LMWH injections in patients with cancer-associated VTE. Methods Consecutive patients with active cancer and objectively confirmed symptomatic proximal deep vein thrombosis and/or pulmonary embolism, treated at three Dutch hospitals and one Spanish hospital, were included to evaluate continuation LMWH therapy during LMWH treatment. Patients were excluded when they received other anticoagulants, were lost to follow-up, or experienced a venous catheter-associated thrombosis. Results A total of 372 patients were analyzed during LMWH treatment for a maximum of 180 days. The cumulative incidence of discontinuation was 21% (95% confidence interval [CI] 17-25) after a median period of 90 days (interquartile range 60-120 days). Only female sex was found to be significantly associated with premature LMWH discontinuation (odds ratio 1.6; 95% CI 1.03-2.5). Thirty patients (8.1%) developed recurrent VTE, 30 patients (8.3%) suffered a major bleed, and 106 patients (28%) died. Conclusion Our study reveals that one of five patients with cancer-associated VTE stopped LMWH injections because of side-effects. This finding provides relevant background information for current clinical trials investigating the efficacy and safety of direct oral anticoagulants as compared with LMWH.

PO-07 - Excluding pulmonary embolism in cancer patients using the Wells rule and age-adjusted D-dimer testing: an individual patient data meta-analysis.

INTRODUCTION: Among patients with clinically suspected pulmonary embolism (PE), imaging and anticoagulant treatment can be safely withheld in approximately one-third of patients based on the combination of a "PE unlikely" Wells score and a D-dimer below the age-adjusted threshold. The clinical utility of this diagnostic approach in cancer patients is less clear. AIM: To evaluate the efficiency and failure rate of the original and simplified Wells rules in combination with age-adjusted D-dimer testing in patients with active cancer. MATERIALS AND METHODS: Individual patient data were used from 6 large prospective studies in which the diagnostic management of PE was guided by the original Wells rule and D-dimer testing. Study physicians classified patients as having active cancer if they had new, recurrent, or progressive cancer (excluding basal-cell or squamous-cell skin carcinoma), or cancer requiring treatment in the last 6 months. We evaluated the dichotomous Wells rule and its simplified version (Table). The efficiency of the algorithm was defined as the proportion of patients with a "PE unlikely" Wells score and a negative age-adjusted D-dimer, defined by a D-dimer below the threshold of a patient's age times 10 µg/L in patients aged ≥51 years. A diagnostic failure was defined as a patient with a "PE unlikely" Wells score and negative age-adjusted D-dimer who had symptomatic venous thromboembolism during 3 months follow-up. A one-stage random effects meta-analysis was performed to estimate the efficiency and failure. RESULTS: The dataset comprised 938 patients with active cancer with a mean age of 63 years. The most frequent cancer types were breast (13%), gastrointestinal tract (11%), and lung (8%). The type of cancer was not specified in 42%. The pooled PE prevalence was 29% (95% CI 25-32). PE could be excluded in 122 patients based on a "PE unlikely" Wells score and a negative age-adjusted D-dimer (efficiency 13%; 95% CI 11-15). Two of 122 patients were diagnosed with non-fatal symptomatic venous thromboembolism during follow-up (failure rate 1.5%; 95% CI 0.13-14.8). The simplified Wells score in combination with a negative age-adjusted D-dimer had an efficiency of 3.9% (95% CI 2.0-7.6) and a failure rate of 2.4% (95% CI 0.3-15). CONCLUSIONS: Among cancer patients with clinically suspected PE, imaging and anticoagulant treatment can be withheld in 1 out of every 8 patients by the original Wells rule and age-adjusted D-dimer testing. The simplified Wells rule was neither efficient nor safe in this population.

PO-29 - Age-adjusted D-dimer cutoff level increases the number of cancer patients in who pulmonary embolism can be safely excluded without CT-PA imaging: The ADJUST-PE cancer substudy.

INTRODUCTION: Patients with cancer frequently present with suspected pulmonary embolism (PE). The D-dimer test is less useful to rule out PE in cancer patients due to a lower specificity, whereas the safety of the combination of a clinical decision rule (CDR) and D-dimer test to rule out PE in these patients is unclear. In the general population, use of an age-adjusted cutoff for D-dimer in combination with a CDR has been shown to improve specificity in the diagnosis of PE. AIM: We prospectively analysed the safety and efficacy of the age-adjusted D-dimer (defined as age×10 in patients >50 years) combined with CDR for the exclusion of PE in patients with cancer. MATERIALS AND METHODS: We conducted a multicenter multinational prospective management outcome study in 19 centers in Belgium, France, The Netherlands and Switzerland, the ADJUST-PE study, to validate an age-adjusted D-dimer cut-off in patients with suspected PE. The performance of the age-adjusted D-dimer cut-off and CDR was compared between patients with and without cancer. The primary outcome was the rate of adjudicated thromboembolic events during three-month follow-up. RESULTS: Of the 3,324 patients with suspected PE, 429 (12.9%) patients had cancer. Cancer patients were older and more often had surgery or immobilisation. The prevalence of PE was 108/429 (25.2%) in cancer patients and 522/2894 (18%) in patients without cancer, p<0.001. Among cancer patients with an unlikely CDR, 27/274 (9.9%) had a D-Dimer <500 µg/L as compared with 19.7% using the age-adjusted D-dimer cut-off; in patients without cancer, these rates were 30.1% and 41.9%, respectively. The percentage of cancer patients in whom PE could be excluded based on CDR and age-adjusted D-dimer doubled from 6.3% to 12.6%. None of these cancer patients had a venous thromboembolic event during three-month follow-up, thus the failure rate was 0.0% (95% CI 0.0-6.9%). CONCLUSIONS: Compared with the usual cut-off, the age-adjusted D-dimer cut-off doubles the proportion of patients with cancer in whom PE can be safely excluded by CDR and D-dimer without need for CTPA imaging.

Risk of recurrent venous thromboembolism and major hemorrhage in cancer-associated incidental pulmonary embolism among treated and untreated patients: a pooled analysis of 926 patients.

UNLABELLED: ESSENTIALS: We performed a pooled analysis of 926 patients with cancer-associated incidental pulmonary embolism (IPE). Vitamin K antagonists (VKA) are associated with a higher risk of major hemorrhage. Recurrence risk is comparable after subsegmental and more proximally localized IPE. Our results support low molecular weight heparins over VKA and similar management of subsegmental IPE. BACKGROUND: Incidental pulmonary embolism (IPE) is defined as pulmonary embolism (PE) diagnosed on computed tomography scanning not performed for suspected PE. IPE has been estimated to occur in 3.1% of all cancer patients and is a growing challenge for clinicians and patients. Nevertheless, knowledge about the treatment and prognosis of cancer-associated IPE is scarce. We aimed to provide the best available evidence on IPE management. METHODS: Incidence rates of symptomatic recurrent venous thromboembolism (VTE), major hemorrhage, and mortality during 6-month follow-up were pooled using individual patient data from studies identified by a systematic literature search. Subgroup analyses based on cancer stage, thrombus localization, and management were performed. RESULTS: In 926 cancer patients with IPE from 11 cohorts, weighted pooled 6-month risks of recurrent VTE, major hemorrhage and mortality were 5.8% (95% confidence interval [CI] 3.7-8.3%), 4.7% (95% CI 3.0-6.8%), and 37% (95% CI 28-47%). VTE recurrence risk was comparable under low molecular weight heparins (LMWH) and vitamin K antagonists (VKAs) (6.2% vs. 6.4%; hazard ratio [HR] 0.9; 95% CI 0.3-3.1), while 12% in untreated patients (HR 2.6; 95% CI 0.91-7.3). Risk of major hemorrhage was higher under VKAs than under LMWH (13% vs. 3.9%; HR 3.9; 95% CI 1.6-10). VTE recurrence risk was comparable in patients with an subsegmental IPE and those with a more proximally localized IPE (HR 1.1; 95% CI 0.50-2.4). CONCLUSION: These results support the current recommendation to anticoagulate cancer-associated IPE with LMWH and argue against different management of subsegmental IPE.

A simple decision rule including D-dimer to reduce the need for computed tomography scanning in patients with suspected pulmonary embolism.

BACKGROUND: An 'unlikely' clinical decision rule with a negative D-dimer result safely excludes pulmonary embolism (PE) in 30% of presenting patients. We aimed to simplify this diagnostic approach and to increase its efficiency. METHODS: Data for 723 consecutive patients with suspected PE were analyzed (prevalence of PE, 22%). After constructing a logistic regression model with the D-dimer test result and items from the Wells' score, we identified the most prevalent combinations of influential items and selected new D-dimer positivity thresholds. The performance was separately validated with data from 2785 consecutive patients with suspected PE. RESULTS: Three Wells items significantly added incremental value to the D-dimer test: hemoptysis, signs of deep vein thrombosis and 'PE most likely'. Based on the most frequent combinations of these three items, we identified two groups: (i) none of these three items positive (41%); (ii) one or more of these items positive (59%). When applying a 1000 µg/L D-dimer threshold in group 1 and 500 µg/L in group 2, PE could be excluded without CT scanning in 36%, at a false-negative rate of 1.2% (95%, 0.04-3.3%). In the validation set, these proportions were 46% and 1.9% (95% CI, 1.2-2.7%), respectively. Using the conventional Wells score with a normal D-dimer result, these rates were, respectively, 22% and 0.6% (95% CI, 0.10-2.4%). CONCLUSION: Combining Wells items with the D-dimer test resulted in a simplified decision rule, which reduces the need for CT scanning in patients with suspected PE. A prospective validation is required before it can be implemented in clinical practice.

The post-PE syndrome: a new concept for chronic complications of pulmonary embolism.

Long-term follow-up studies have consistently demonstrated that after an episode of acute pulmonary embolism (PE), half of patients report functional limitations and/or decreased quality of life up to many years after the acute event. Incomplete thrombus resolution occurs in one-fourth to one-third of patients. Further, pulmonary artery pressure and right ventricular function remain abnormal despite adequate anticoagulant treatment in 10-30% of patients, and 0.5-4% is diagnosed with chronic thromboembolic pulmonary hypertension (CTEPH) which represents the most severe long term complication of acute PE. From these numbers, it seems that CTEPH itself is the extreme manifestation of a much more common phenomenon of permanent changes in pulmonary artery flow, pulmonary gas exchange and/or cardiac function caused by the acute PE and associated with dyspnea and decreased exercise capacity, which in analogy to post-thrombotic syndrome after deep vein thrombosis could be referred to as the post-pulmonary embolism syndrome. The acknowledgement of this syndrome would both be relevant for daily clinical practice and also provide a concept that aids in further understanding of the pathophysiology of CTEPH. In this clinically oriented review, we discuss the established associations and hypotheses between the process of thrombus resolution or persistence, lasting hemodynamic changes following acute PE as well as the consequences of a PE diagnosis on long-term physical performance and quality of life.

Meta-analysis of the efficacy and safety of new oral anticoagulants in patients with cancer-associated acute venous thromboembolism.

INTRODUCTION: Treatment of acute venous thromboembolism (VTE) in cancer patients is challenging, owing to a high risk of recurrent VTE and bleeding complications. The anticoagulants of choice are low molecular weight heparins (LMWHs), because of a proven higher efficacy than vitamin K antagonists (VKAs) and a similar bleeding profile. The recently introduced new oral anticoagulants (NOACs) have the potential to be alternative options for these patients, as these drugs share practical advantages with LMWH, are administered orally, and had similar efficacy to VKAs but a lower bleeding risk in phase 3 studies in the general VTE population. METHODS: A systematic literature search was performed to identify phase 3 trials investigating NOACs for the treatment of VTE. The efficacy outcome was recurrent VTE, and the safety outcome was major and clinically relevant non-major bleeding. Pooled incidence rates and risk ratios (RRs) were calculated for cancer patients and non-cancer patients separately. RESULTS AND DISCUSSION: Five studies were included, with 19 060 patients, of whom 973 (5.1%) had active cancer. The pooled incidence rates of recurrent VTE were 4.1% (95% confidence interval [CI] 2.6-6.0) in cancer patients treated with NOACs, and 6.1% (95% CI 4.1-8.5) in patients treated with VKAs (RR 0.66, 95% CI 0.38-1.2). The pooled incidence rates of major or non-major clinically relevant bleeding were 15% (95% CI 12-18) in cancer patients treated with NOACs, and 16% (95% CI 9.9-22) in patients treated with VKAs (RR 0.94, 95% CI 0.70-1.3). These results form a solid basis for the initiation of a head-to-head comparison of NOACs with LMWH in cancer patients.

Effectiveness and safety of novel oral anticoagulants as compared with vitamin K antagonists in the treatment of acute symptomatic venous thromboembolism: a systematic review and meta-analysis.

INTRODUCTION: New direct oral anticoagulants (NOACs) constitute a novel treatment option for acute venous thromboembolism (VTE), with practical advantages. Individual studies have demonstrated comparable efficacy to that of vitamin K antagonists (VKAs) and have suggested a more favorable safety profile . We performed a meta-analysis to determine the efficacy and safety of NOACs as compared with those of VKAs in patients with acute VTE. METHODS: We searched MEDLINE, EMBASE, the Cochrane Database of Systematic Reviews and the Clinical Trials Registry up to October 2013. Eligible studies included phase 3 trials comparing NOACs with VKAs in patients with acute VTE. Relative risks (RRs), absolute risk differences and numbers needed to treat (NNTs) to prevent one event were calculated for recurrent VTE, fatal pulmonary embolism (PE), overall mortality, major bleeding, and other bleeding complications, with random-effects models. RESULTS: Five studies were included, investigating four NOACs (rivaroxaban, dabigatran, apixaban, and edoxaban) in 24 455 patients with acute VTE. RRs for recurrent VTE, fatal PE and overall mortality for NOACs vs. VKAs were 0.88 (95% confidence interval [CI] 0.74-1.05), 1.02 (95% CI 0.39-5.96), and 0.97 (95% CI 0.83-1.14), respectively. The RR for major bleeding was 0.60 (95% CI 0.41-0.88). The NNT with NOACs instead of VKA to prevent one major bleed was 149. The RR and NNT for fatal bleeding were 0.36 (95% CI 0.15-0.87) and 1111. A fixed-effect network analysis did not demonstrate significant differences between individual NOACs and rivaroxaban. CONCLUSIONS: NOACs have comparable efficacy to that of VKAs, and are associated with a significantly lower risk of bleeding complications, although the NNT to prevent one major bleed was relatively high.

Impact of chronic kidney disease on the risk of clinical outcomes in patients with cancer-associated venous thromboembolism during anticoagulant treatment.

BACKGROUND: Information on recurrent venous thromboembolic events (VTEs) and major bleeding risks during anticoagulant treatment in patients with cancer-associated VTEs and chronic kidney disease (CKD) is scarce, although it is of relevance in establishing better tailored management strategies in these patients. OBJECTIVES: We compared risks of recurrent VTEs and major bleeds in cancer-associated VTE patients with and without CKD. METHODS: A total of 1684 patients diagnosed with a cancer-associated VTE between 2001 and 2011 were followed for 180 days after VTE diagnosis. Patients were treated mainly with low-molecular-weight heparin (LMWH) or vitamin-K antagonists (VKA). Primary outcomes were recurrent VTE and major bleeding. Secondary outcome was fatal bleeding. RESULTS: Recurrent VTEs occurred in 15.9/100 patient years (py) in patients without CKD (eGFR > 60 mL min(-1) ), 19.5/100 py in those with CKD stage 3A (eGFR 45-60 mL min(-1) ), 14.9/100 py in those with CKD 3B (eGFR 30-45 mL min(-1) ), and 6.8/100 py in patients with CKD 4-5 (eGFR < 30 mL min(-1) ). Major bleeding occurred in 11.4/100 py in patients without CKD, 18.5/100 py in those with CKD stage 3A, 16.0/100 py in those with CKD 3B, and 40.8/100 py in patients with CKD 4-5. Fatal bleeding occurred in 1.1/100 py, 3.4/100 py, 6.3/100 py and 15.7/100 py, respectively. These increased bleeding risks in CKD patients were mainly observed in those on LMWH treatment, not VKA. CONCLUSIONS: The risk of major bleeding was increased in CKD patients with VTE and cancer, and was most prominent in those treated with LMWH and an eGFR < 30 mL min(-1) . These results indicate that LMWH should be used with caution in this specific population.

Computed tomography-assessed right ventricular dysfunction and risk stratification of patients with acute non-massive pulmonary embolism: systematic review and meta-analysis.

BACKGROUND: The ability of computed tomography (CT)-assessed right ventricular dysfunction (RVD) to identify normotensive patients with acute pulmonary embolism (PE) at high risk of mortality or adverse outcome lacks clarity. METHODS AND RESULTS: We performed a systematic review and a meta-analysis of studies in normotensive patients with acute PE to assess the prognostic value of CT-assessed RVD for death and a predefined composite outcome of PE-related complications. We conducted unrestricted searches of MEDLINE and EMBASE from 1980 to March 2013, and used the terms 'computed tomography', 'pulmonary embolism', and 'prognos*'. We used a random-effects model to pool study results, funnel-plot inspection to evaluate for publication bias, and I(2) testing to assess for heterogeneity. The analysis included data from 10 studies (2288 patients). Overall, 99 of 1268 patients with RVD assessed by CT died (7.8%; 95% confidence interval [CI] 6.3-9.3) as compared with 52 of 1020 without RVD (5.1%; 95% CI 3.7-6.4). CT-assessed RVD had significant associations with mortality (odds ratio [OR] 1.8; 95% CI 1.3-2.6), with death resulting from PE (OR 7.4; 95% CI 1.4-39.5), and with PE-related complications (OR 2.4; 95% CI 1.2-4.7). Pooled likelihood ratios (LRs) were not extreme (negative LR 0.71; 95% CI 0.57-0.89; and positive LR 1.27; 95% CI 1.12-1.43). CONCLUSIONS: Although RVD assessed by CT showed an association with an increased risk of mortality in patients with hemodynamically stable PE, it resulted in only small increases in the ability to classify risk.

Variable D-dimer thresholds for diagnosis of clinically suspected acute pulmonary embolism.

BACKGROUND: Computed tomography pulmonary angiography (CTPA) is frequently requested using diagnostic algorithms for suspected pulmonary embolism (PE). For suspected deep vein thrombosis, it was recently shown that doubling the D-dimer threshold in patients with low pretest probability safely decreased the number of ultrasonograms. We evaluated the safety and efficiency of a similar strategy in patients with suspected PE. METHODS: We performed a post-hoc analysis of 2213 consecutive patients of two cohort studies with suspected PE who were managed according to current standards: PE ruled out in case of unlikely probability (Wells rule ≤ 4 points) and a D-dimer level < 0.5 µg mL(-1) . CTPA was performed in all other cases. All patients were followed for 3 months. We calculated 3-month venous thromboembolism (VTE) incidence and the number of required CTPAs for selective D-dimer thresholds in patients with low clinical probability (< 2 points, D-dimer threshold < 1.0 µg mL(-1) ) and intermediate probability (2-6 points, D-dimer threshold < 0.5 µg mL(-1) ). RESULTS: Using standard management, PE could be excluded without CTPA in 26% of patients, with a 3-month VTE incidence of 0.88% (95% confidence interval [CI] 0.29-2.1%). Using selective D-dimer thresholds, PE could be excluded without CTPA in 36% of patients, with a 3-month VTE incidence of 2.1% (95% CI 1.2-3.4%) in patients managed without CTPA, an increase of 1.2 percentage points (95% CI -0.3 to 2.2). CONCLUSIONS: Applying selective D-dimer thresholds reduces the need for CTPA by 11 percentage points but is associated with an increased failure rate. Prospective studies should evaluate the safety and net clinical benefit of this approach.

Long-term clinical course of acute pulmonary embolism.

The long-term clinical course of acute pulmonary embolism (PE) is complicated by high rates of serious adverse events, both before and after cessation of anticoagulant therapy. These adverse events include recurrent venous thromboembolism, chronic thromboembolic pulmonary hypertension, arterial thrombotic events and increased risk of death, all compared to patients without thromboembolic disease. Several pharmacological options are available that may beneficially influence patients' prognosis. Nonetheless, because of insufficient knowledge of the benefit-to-harm ratio of these pharmacological agents, unambiguous recommendations are scarcely available. This review will cover the epidemiological aspects of the various possible complications in the long-term clinical course of acute PE as well as the latest evidence on preventive strategies. In addition, the unresolved issues regarding frequency, duration and focus of medical follow-up after acute PE are discussed.