Petra M.G. Erkens

Age-adjusted D-dimer cutoff levels to rule out pulmonary embolism: the ADJUST-PE study.

IMPORTANCE D-dimer measurement is an important step in the diagnostic strategy of clinically suspected acute pulmonary embolism (PE), but its clinical usefulness is limited in elderly patients. OBJECTIVE To prospectively validate whether an age-adjusted D-dimer cutoff, defined as age × 10 in patients 50 years or older, is associated with an increased diagnostic yield of D-dimer in elderly patients with suspected PE. DESIGN, SETTINGS, AND PATIENTS A multicenter, multinational, prospective management outcome study in 19 centers in Belgium, France, the Netherlands, and Switzerland between January 1, 2010, and February 28, 2013. INTERVENTIONS All consecutive outpatients who presented to the emergency department with clinically suspected PE were assessed by a sequential diagnostic strategy based on the clinical probability assessed using either the simplified, revised Geneva score or the 2-level Wells score for PE; highly sensitive D-dimer measurement; and computed tomography pulmonary angiography (CTPA). Patients with a D-dimer value between the conventional cutoff of 500 µg/L and their age-adjusted cutoff did not undergo CTPA and were left untreated and formally followed-up for a 3-month period. MAIN OUTCOMES AND MEASURES The primary outcome was the failure rate of the diagnostic strategy, defined as adjudicated thromboembolic events during the 3-month follow-up period among patients not treated with anticoagulants on the basis of a negative age-adjusted D-dimer cutoff result. RESULTS Of the 3346 patients with suspected PE included, the prevalence of PE was 19%. Among the 2898 patients with a nonhigh or an unlikely clinical probability, 817 patients (28.2%) had a D-dimer level lower than 500 µg/L (95% CI, 26.6%-29.9%) and 337 patients (11.6%) had a D-dimer between 500 µg/L and their age-adjusted cutoff (95% CI, 10.5%-12.9%). The 3-month failure rate in patients with a D-dimer level higher than 500 µg/L but below the age-adjusted cutoff was 1 of 331 patients (0.3% [95% CI, 0.1%-1.7%]). Among the 766 patients 75 years or older, of whom 673 had a nonhigh clinical probability, using the age-adjusted cutoff instead of the 500 µg/L cutoff increased the proportion of patients in whom PE could be excluded on the basis of D-dimer from 43 of 673 patients (6.4% [95% CI, 4.8%-8.5%) to 200 of 673 patients (29.7% [95% CI, 26.4%-33.3%), without any additional false-negative findings. CONCLUSIONS AND RELEVANCE Compared with a fixed D-dimer cutoff of 500 µg/L, the combination of pretest clinical probability assessment with age-adjusted D-dimer cutoff was associated with a larger number of patients in whom PE could be considered ruled out with a low likelihood of subsequent clinical venous thromboembolism. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01134068.

Performance of 4 Clinical Decision Rules in the Diagnostic Management of Acute Pulmonary Embolism: A Prospective Cohort Study

BACKGROUND Several clinical decision rules (CDRs) are available to exclude acute pulmonary embolism (PE), but they have not been directly compared. OBJECTIVE To directly compare the performance of 4 CDRs (Wells rule, revised Geneva score, simplified Wells rule, and simplified revised Geneva score) in combination with d-dimer testing to exclude PE. DESIGN Prospective cohort study. SETTING 7 hospitals in the Netherlands. PATIENTS 807 consecutive patients with suspected acute PE. INTERVENTION The clinical probability of PE was assessed by using a computer program that calculated all CDRs and indicated the next diagnostic step. Results of the CDRs and d-dimer tests guided clinical care. MEASUREMENTS Results of the CDRs were compared with the prevalence of PE identified by computed tomography or venous thromboembolism at 3-month follow-up. RESULTS Prevalence of PE was 23%. The proportion of patients categorized as PE-unlikely ranged from 62% (simplified Wells rule) to 72% (Wells rule). Combined with a normal d-dimer result, the CDRs excluded PE in 22% to 24% of patients. The total failure rates of the CDR and d-dimer combinations were similar (1 failure, 0.5% to 0.6% [upper-limit 95% CI, 2.9% to 3.1%]). Even though 30% of patients had discordant CDR outcomes, PE was not detected in any patient with discordant CDRs and a normal d-dimer result. LIMITATION Management was based on a combination of decision rules and d-dimer testing rather than only 1 CDR combined with d-dimer testing. CONCLUSION All 4 CDRs show similar performance for exclusion of acute PE in combination with a normal d-dimer result. This prospective validation indicates that the simplified scores may be used in clinical practice. PRIMARY FUNDING SOURCE Academic Medical Center, VU University Medical Center, Rijnstate Hospital, Leiden University Medical Center, Maastricht University Medical Center, Erasmus Medical Center, and Maasstad Hospital.

Clinical decision rules for excluding pulmonary embolism: a meta-analysis.

BACKGROUND Clinical probability assessment is combined with d-dimer testing to exclude pulmonary embolism (PE). PURPOSE To compare the test characteristics of gestalt (a physicians unstructured estimate) and clinical decision rules for evaluating adults with suspected PE and assess the failure rate of gestalt and rules when used in combination with d-dimer testing. DATA SOURCES Articles in MEDLINE and EMBASE in English, French, German, Italian, Spanish, or Dutch that were published between 1966 and June 2011. STUDY SELECTION 3 reviewers, working in pairs, selected prospective studies in consecutive patients suspected of having PE. Studies had to estimate the probability of PE by using gestalt or a decision rule and verify the diagnosis by using an appropriate reference standard. DATA EXTRACTION Data on study characteristics, test performance, and prevalence were extracted. Reviewers constructed 2 × 2 tables and assessed the methodological quality of the studies. DATA SYNTHESIS 52 studies, comprising 55 268 patients, were selected. Meta-analysis was performed on studies that used gestalt (15 studies; sensitivity, 0.85; specificity, 0.51), the Wells rule with a cutoff value less than 2 (19 studies; sensitivity, 0.84; specificity, 0.58) or 4 or less (11 studies; sensitivity, 0.60; specificity, 0.80), the Geneva rule (5 studies; sensitivity, 0.84; specificity, 0.50), and the revised Geneva rule (4 studies; sensitivity, 0.91; specificity, 0.37). An increased prevalence of PE was associated with higher sensitivity and lower specificity. Combining a decision rule or gestalt with d-dimer testing seemed safe for all strategies, except when the less-sensitive Wells rule (cutoff value ≤4) was combined with less-sensitive qualitative d-dimer testing. LIMITATIONS Studies had substantial heterogeneity due to prevalence of PE and differences in threshold. Many studies (63%) had potential bias due to differential disease verification. CONCLUSION Clinical decision rules and gestalt can safely exclude PE when combined with sensitive d-dimer testing. The authors recommend standardized rules because gestalt has lower specificity, but the choice of a particular rule and d-dimer test depend on both prevalence and setting.

Safe exclusion of pulmonary embolism using the Wells rule and qualitative D-dimer testing in primary care: prospective cohort study

Objective To validate the use of the Wells clinical decision rule combined with a point of care D-dimer test to safely exclude pulmonary embolism in primary care. Design Prospective cohort study. Setting Primary care across three different regions of the Netherlands (Amsterdam, Maastricht, and Utrecht). Participants 598 adults with suspected pulmonary embolism in primary care. Interventions Doctors scored patients according to the seven variables of the Wells rule and carried out a qualitative point of care D-dimer test. All patients were referred to secondary care and diagnosed according to local protocols. Pulmonary embolism was confirmed or refuted on the basis of a composite reference standard, including spiral computed tomography and three months’ follow-up. Main outcome measures Diagnostic accuracy (sensitivity and specificity), proportion of patients at low risk (efficiency), number of missed patients with pulmonary embolism in low risk category (false negative rate), and the presence of symptomatic venous thromboembolism, based on the composite reference standard, including events during the follow-up period of three months. Results Pulmonary embolism was present in 73 patients (prevalence 12.2%). On the basis of a threshold Wells score of ≤4 and a negative qualitative D-dimer test result, 272 of 598 patients were classified as low risk (efficiency 45.5%). Four cases of pulmonary embolism were observed in these 272 patients (false negative rate 1.5%, 95% confidence interval 0.4% to 3.7%). The sensitivity and specificity of this combined diagnostic approach was 94.5% (86.6% to 98.5%) and 51.0% (46.7% to 55.4%), respectively. Conclusion A Wells score of ≤4 combined with a negative qualitative D-dimer test result can safely and efficiently exclude pulmonary embolism in primary care.

Safety of outpatient treatment in acute pulmonary embolism.

See also Baglin T. Fifty per cent of patients with pulmonary embolism can be treated as outpatients. This issue, pp 2404–5; Kovacs MJ, Hawel JD, Rekman JF, Lazo‐Langner A. Ambulatory management of pulmonary embolism: a pragmatic evaluation. This issue, pp 2406–11.

Benchmark for time in therapeutic range in venous thromboembolism: a systematic review and meta-analysis.

Introduction The percentage of time within the target INR range 2.0 to 3.0 (TTR) in patients treated with vitamin K antagonists varies considerably among efficacy-studies of novel anticoagulants. In order to properly asses the quality of anticoagulant control in upcoming cost-effectiveness studies and real life registries this systematic review reports a benchmark of TTR for different treatment durations in patients with venous thromboembolism and discusses ways to calculate TTR. Methods Medline and Embase were searched for studies published between January 1990 and May 2012. Randomized controlled trials and cohort studies reporting the TTR in patients with objectively confirmed venous thromboembolism treated with vitamin K antagonists (VKA) were eligible. Duplicate reports, studies only reporting INR during initial treatment or with VKA treatment less than 3 months were excluded. Three authors assessed trials for inclusion and extracted data independently. Discrepancies were resolved by discussion between the reviewers. A meta-analysis was performed by calculating a weighted mean, based on the number of participants in each included study, for each time-period in which the TTR was measured since the confirmation of the diagnosis of VTE. Results Forty studies were included (26064 patients). The weighted means of TTR were 54.0% in the first month since the start of treatment, 55.6% in months 1 to 3, 60.0% in months 2 to 3, 60.0% in the months1 to 6+ and 75.2% in months 4 to 12+. Five studies reported TTR in classes. The INR in these studies was ≥67% of time in therapeutic range in 72.0% of the patients. Conclusion Reported quality of VKA treatment is highly dependent on the time-period since the start of treatment, with TTR ranging from approximately 56% in studies including the 1st month to 75% in studies excluding the first 3 months.

Does the Pulmonary Embolism Severity Index accurately identify low risk patients eligible for outpatient treatment

INTRODUCTION The pulmonary embolism severity index (PESI) and the recently derived simplified PESI prognostic model have been developed to estimate the risk of 30-day mortality in patients with acute PE. We sought to assess if the PESI and simplified PESI prognostic models can accurately identify adverse events and to determine the rates of events in patients treated as outpatients. METHODS A retrospective cohort study of patients with acute pulmonary embolism (PE) presenting at the Ottawa Hospital (Canada) was conducted between 1 January 2007 and 31 December 2008. RESULTS Two hundred and forty three patients were included. A total of 118 (48.6%) and 81 (33.3%) were classified as low risk patients using the original and simplified PESI prognostic models respectively. None of the low risk patients died within the 3months of follow-up. One hundred and fifteen (47.3%) patients were safely treated as outpatients with no deaths or bleeding episodes and only 1 recurrent event within the first 14days or after 30days of follow-up. Thirty four (29.6%) of these outpatients were classified as high risk patients according to the original PESI and 54 (47.0%) to the simplified PESI prognostic model. CONCLUSION Both PESI strategies accurately identify patients with acute PE who are at low risk and high risk for short-term adverse events. However, 30 to 47% of patients with acute PE and a high risk PESI score were safely managed as outpatients. Future research should be directed at developing tools that predict which patients would benefit from inpatient management.

Quality of life after pulmonary embolism as assessed with SF-36 and PEmb-QoL

INTRODUCTION Although quality of life (QoL) is recognized as an important indicator of the course of a disease, it has rarely been addressed in studies evaluating the outcome of care for patients with pulmonary embolism (PE). This study primarily aimed to evaluate the QoL of patients with acute PE in comparison to population norms and to patients with other cardiopulmonary diseases, using a generic QoL questionnaire. Secondary, the impact of time period from diagnosis and clinical patient characteristics on QoL was assessed, using a disease-specific questionnaire. METHODS QoL was assessed in 109 consecutive out-patients with a history of objectively confirmed acute PE (mean age 60.4 ± 15.0 years, 56 females), using the generic Short Form-36 (SF-36) and the disease specific Pulmonary Embolism Quality of Life questionnaire (PEmb-QoL). The score of the SF-36 were compared with scores of the general Dutch population and reference populations with chronic obstructive pulmonary disease (COPD), congestive heart failure (CHF), a history of acute myocardial infarction (AMI), derived from the literature. Scores on the SF-35 and PEmb-QoL were used to evaluate QoL in the short-term and long-term clinical course of patients with acute PE. In addition, we examined correlations between PEmb-QoL scores and clinical patient characteristics. RESULTS Compared to scores of the general Dutch population, scores of PE patients were worse on several subscales of the SF-36 (social functioning, role emotional, general health (P<0.001), role physical and vitality (P<0.05)). Compared to patients with COPD and CHF, patients with PE scored higher (=better) on all subscales of the SF-36 (P ≤ 0.004) and had scores comparable with patients with AMI the previous year. Comparing intermediately assessed QoL with QoL assessed in long-term follow-up, PE patients scored worse on SF-36 subscales: physical functioning, social functioning, vitality (P<0.05), and on the PEmb-QoL subscales: emotional complaints and limitations in ADL (P ≤ 0.03). Clinical characteristics did not correlate with QoL as measured by PEmb-QoL. CONCLUSION Our study demonstrated an impaired QoL in patients after treatment of PE. The results of this study provided more knowledge about QoL in patients treated for PE.

Patient-reported treatment satisfaction with oral rivaroxaban versus standard therapy in the treatment of pulmonary embolism; results from the EINSTEIN PE trial

INTRODUCTION Rivaroxaban is an oral, direct Factor Xa inhibitor, approved for the treatment of pulmonary embolism (PE) and deep vein thrombosis (DVT) and the secondary prevention of recurrent PE and DVT as a fixed-dose, monotherapy regimen that does not require initial heparinisation, routine coagulation monitoring or dose adjustment. Approval in this indication was supported by results from EINSTEIN PE, a large, randomised, open-label study that compared rivaroxaban with enoxaparin/vitamin K antagonist (VKA) therapy in patients with acute symptomatic PE with or without DVT. MATERIALS AND METHODS Patient-reported treatment satisfaction was evaluated in a predefined subanalysis of EINSTEIN PE to enable monitoring and optimisation of patient-reported outcomes and, therefore, patient compliance. As part of EINSTEIN PE, 2,397 patients in seven countries were asked to complete a validated measure of treatment satisfaction, the Anti-Clot Treatment Scale (ACTS) throughout the duration of treatment (up to 12 months). RESULTS Patients reported greater satisfaction in the rivaroxaban treatment arm as compared with the enoxaparin/VKA treatment arm. Treatment with rivaroxaban was reported as being significantly less burdensome than enoxaparin/VKA therapy, and the benefits of treatment were significantly greater. CONCLUSION Rivaroxaban treatment resulted in improved treatment satisfaction compared with enoxaparin/VKA in PE patients, particularly in reducing patient-reported anticoagulation burden.

Self-reported adherence to anticoagulation and its determinants using the Morisky medication adherence scale

BACKGROUND Direct oral anticoagulants (DOACs) are used for treatment of venous thromboembolism (VTE) and stroke prevention in atrial fibrillation (AF). Given the shorter half-life and lack of laboratory monitoring compared to vitamin-K antagonists (VKAs), adequate adherence to DOACs is important. Reported anticoagulation adherence is unclear in clinical practice. OBJECTIVES To assess self-reported anticoagulation adherence in a tertiary center anticoagulation clinic. PATIENTS/METHODS Cross-sectional study of patients on oral anticoagulants (VKAs, rivaroxaban, dabigatran and apixaban). Anticoagulation adherence was assessed using the 4-item Morisky score. Baseline characteristics were evaluated for association with adherence. RESULTS Five hundred patients completed the survey; 74% were on VKAs and 26% on DOACs: rivaroxaban 102 (79%); dabigatran 26 (19%); apixaban 2 (2%). Main indications for anticoagulation were VTE (72%) and AF (18%). Self-reported anticoagulation adherence using the 4-item Morisky scale was 56.2% for patients on VKAs and 57.1% for patients on DOACs. Predictors of anticoagulation adherence were age (OR=1.02; 95% CI:1.01-1.03), female gender (OR=1.58; 95% CI:1.10-2.27), use of additional oral medications (OR=2.78; 95% CI:1.67-4.63), and retired employment status (OR=2.31; 95% CI:1.51-3.55). In backward selection multivariate analyses age, female gender and use of other oral medications remained significantly associated with anticoagulation adherence. CONCLUSIONS Self-reported anticoagulation adherence was similar between VKAs and DOACs. Until laboratory assays are universally available to evaluate DOAC adherence, physicians should emphasize the importance of anticoagulation adherence at each patient encounter. The Morisky scale provides simple assessment of anticoagulation adherence; however it has not yet been validation for this purpose.