Frederikus A. Klok

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

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.

Prospective cardiopulmonary screening program to detect chronic thromboembolic pulmonary hypertension in patients after acute pulmonary embolism

Background Chronic thromboembolic pulmonary hypertension after pulmonary embolism is associated with high morbidity and mortality. Understanding the incidence of chronic thromboembolic pulmonary hypertension after pulmonary embolism is important for evaluating the need for screening but is also a subject of debate because of different inclusion criteria among previous studies. We determined the incidence of chronic thromboembolic pulmonary hypertension after acute pulmonary embolism and the utility of a screening program for this disease. Design and Methods We conducted a cohort screening study in an unselected series of consecutive patients (n=866) diagnosed with acute pulmonary embolism between January 2001 and July 2007. All patients who had not been previously diagnosed with pulmonary hypertension (PH) and had survived until study inclusion were invited for echocardiography. Patients with echocardiographic suspicion of PH underwent complete work-up for chronic thromboembolic pulmonary hypertension, including ventilation-perfusion scintigraphy and right heart catheterization. Results After an average follow-up of 34 months of all 866 patients, PH was diagnosed in 19 patients by routine clinical care and in 10 by our screening program; 4 patients had chronic thromboembolic pulmonary hypertension, all diagnosed by routine clinical care. The cumulative incidence of chronic thromboembolic pulmonary hypertension after all cause pulmonary embolism was 0.57% (95% confidence interval [CI] 0.02–1.2%) and after unprovoked pulmonary embolism 1.5% (95% CI 0.08–3.1%). Conclusions Because of the low incidence of chronic thromboembolic pulmonary hypertension after pulmonary embolism and the very low yield of the echocardiography based screening program, wide scale implementation of prolonged follow-up including echocardiography of all patients with pulmonary embolism to detect chronic thromboembolic pulmonary hypertension does not seem to be warranted.

Risk profile and clinical outcome of symptomatic subsegmental acute pulmonary embolism

The clinical significance of subsegmental pulmonary embolism (SSPE) remains to be determined. This study aimed to investigate whether SSPE forms a distinct subset of thromboembolic disease compared with more proximally located pulmonary embolism (PE). We analyzed 3728 consecutive patients with clinically suspected PE. SSPE patients were contrasted to patients with more proximal PE and to patients in whom suspected PE was ruled out, in regards of the prevalence of thromboembolic risk factors and the 3-month risks of recurrent venous thromboembolism (VTE) and mortality. PE was confirmed in 748 patients, of whom 116 (16%) had SSPE; PE was ruled out in 2980 patients. No differences were seen in the prevalence of VTE risk factors, the 3-month risk of recurrent VTE (3.6% vs 2.5%; P = .42), and mortality (10.7% vs 6.5%; P = .17) between patients with SSPE and those with more proximal PE. When compared with patients without PE, aged >60 years, recent surgery, estrogen use, and male gender were found to be independent predictors for SSPE, and patients with SSPE were at an increased risk of VTE during follow-up (hazard ratio: 3.8; 95% CI: 1.3-11.1). This study indicates that patients with SSPE mimic those with more proximally located PE in regards to their risk profile and clinical outcome.

Diagnostic management of acute deep vein thrombosis and pulmonary embolism

Acute deep vein thrombosis (DVT) and pulmonary embolism (PE) represent two expressions of a similar clinical pathological process, often referred to as venous throm‐boembolism (VTE). It has long been recognized that, as clinical signs and symptoms of PE and DVT are not specific for the diagnosis, objective diagnosis in both patients presenting with leg symptoms and those with chest symptoms is mandatory. Since the last review on this subject in this journal in 2009, several large trials have been performed that shed new light on all aspects of the diagnostic management of suspected VTE, especially in the field of simplified clinical decision rules, age‐dependent D‐dimer cut‐offs and magnetic resonance imaging. A literature search covering the period 2007–2012 was performed using the Medline/PubMed database to identify all relevant papers regarding the diagnostic management of acute PE and DVT. Established concepts and the latest evidence on this subject will be the main focus of this review.

Quality of Life in Long-term Survivors of Acute Pulmonary Embolism

BACKGROUND To our knowledge, studies evaluating the quality of life (QoL) in patients with a history of acute pulmonary embolism (PE) are not available, even though QoL is a key outcome component of medical care and a predictor of disease-specific prognosis. METHODS As part of a large follow-up study, the Short Form 36 (SF-36) was presented to consecutive patients who had survived one or more episodes of acute PE. The results of all nine subscales of the SF-36 were compared with sex- and age-adjusted Dutch population norms. Single and multivariate analyses were performed to identify independent determinants of the QoL in our study population. RESULTS The SF-36 was completed by 392 patients. Except for the health change subscale, patients had substantially lower QoL than population norms on all eight remaining subscales. After multivariate analysis, the time interval between the last thromboembolic episode and study inclusion was inversely related to QoL, and significant determinants of poor QoL were prior PE, age, obesity, active malignancy, and cardiopulmonary comorbid conditions. Regression models that included all identified significant determinants proved to be quite modest predictors for QoL in the individual patient. Awareness of illness, coping mechanisms, and self-management behavior might be additional important indicators of QoL in our study population but require further investigation. CONCLUSION We identified several PE- and non-PE-related determinants of QoL in patients with a history of acute PE, which is impaired compared with sex- and age-adjusted population norms. QoL after acute PE should be studied more extensively and added as a standard measure to outcome studies.

Elevated D-dimer levels predict recurrence in patients with idiopathic venous thromboembolism: a meta-analysis

Summary.  Background : The evidence on the optimal duration of treatment in patients with an idiopathic venous thromboembolic event (VTE) is inconclusive. d‐dimer testing to predict recurrent VTE has been evaluated in several studies. Objectives: We performed a meta‐analysis of studies of patients with idiopathic VTE treated with oral anticoagulation therapy (OAT) to assess the prognostic value of elevated d‐dimer levels 1 month after discontinuation of OAT for VTE recurrence. Patients/Methods: The MEDLINE, EMBASE and Cochrane databases were searched to identify relevant studies. Studies were eligible for inclusion if they included patients with idiopathic VTE and in addition reported results for this group separately, had measured d‐dimer approximately 1 month after discontinuation of OAT and had reported on recurrence of VTE. A random‐effects model was used to pool study results. Results: Data from four studies (1539 patients) were included in the current analysis. All studies reported on the number of recurrent events in the normal and elevated d‐dimer groups. Overall, 125 of 751 patients (16.6%) with elevated d‐dimer levels experienced recurrent VTE during the period of follow‐up compared with 57 of 788 patients (7.2%) with normal d‐dimer levels. Elevated d‐dimer levels were significantly associated with recurrent VTE (odds ratio , 2.36; 95% CI, 1.65 to 3.36). Conclusions: Elevated d‐dimer levels measured 1 month after discontinuation of OAT identify patients with idiopathic VTE at higher risk of recurrence.

Diagnostic management of clinically suspected acute pulmonary embolism.

Summary.  Current diagnostic management of hemodynamically stable patients with clinically suspected acute pulmonary embolism (PE) consists of the accurate and rapid distinction between the approximate 20–25% of patients who have acute PE and require anticoagulant treatment, and the overall majority of patients who do not have the disease in question. Clinical outcome studies have demonstrated that, using algorithms with sequential diagnostic tests, PE can be safely ruled out in patients with a clinical probability indicating PE to be unlikely and a normal D‐dimer test result. This obviates the need for additional radiological imaging tests in 20–40% of patients. CT pulmonary angiography (CTPA) has become the first line tool to confirm or exclude the diagnosis of PE in patients with a likely probability of PE or an elevated D‐dimer blood concentration. While single‐row‐detector technology CTPA has a low sensitivity for PE and bilateral compression ultrasound (CUS) of the lower limbs is considered necessary to rule out PE, multi‐row‐detector CTPA is safe to exclude PE without the confirmatory use of CUS.

Magnetic resonance direct thrombus imaging differentiates acute recurrent ipsilateral deep vein thrombosis from residual thrombosis

Accurate diagnostic assessment of suspected ipsilateral recurrent deep vein thrombosis (DVT) is a major clinical challenge because differentiating between acute recurrent thrombosis and residual thrombosis is difficult with compression ultrasonography (CUS). We evaluated noninvasive magnetic resonance direct thrombus imaging (MRDTI) in a prospective study of 39 patients with symptomatic recurrent ipsilateral DVT (incompressibility of a different proximal venous segment than at the prior DVT) and 42 asymptomatic patients with at least 6-month-old chronic residual thrombi and normal D-dimer levels. All patients were subjected to MRDTI. MRDTI images were judged by 2 independent radiologists blinded for the presence of acute DVT and a third in case of disagreement. The sensitivity, specificity, and interobserver reliability of MRDTI were determined. MRDTI demonstrated acute recurrent ipsilateral DVT in 37 of 39 patients and was normal in all 42 patients without symptomatic recurrent disease for a sensitivity of 95% (95% CI, 83% to 99%) and a specificity of 100% (95% CI, 92% to 100%). Interobserver agreement was excellent (κ = 0.98). MRDTI images were adequate for interpretation in 95% of the cases. MRDTI is a sensitive and reproducible method for distinguishing acute ipsilateral recurrent DVT from 6-month-old chronic residual thrombi in the leg veins.

Measurement of Right and Left Ventricular Function by ECG-Synchronized CT Scanning in Patients With Acute Pulmonary Embolism: Usefulness for Predicting Short-term Outcome

BACKGROUND Right ventricular (RV) function is predictive of outcome in patients with acute pulmonary embolism (PE). We assessed the possible incremental value of ventricular function with ECG-synchronized cardiac CT scanning over pulmonary CT scan angiography (CTA) for predicting short-term outcome in patients with suspected acute PE. METHODS The local ethics committee approved the study, and informed consent was obtained. In addition to standard CTA, 430 consecutive patients (193 men, 237 women; age, 55 ± 17 years) with suspected acute PE underwent ECG-synchronized CT scanning to assess ventricular function. RV/left ventricular (LV) function ratio and pulmonary obstruction index were obtained from non-ECG-synchronized CTA. Ventricular function was used to predict adverse events (< 6 weeks). Receiver operating characteristic analysis was performed to determine differences between ECG-synchronized CT scan and CTA in predicting outcome. RESULTS In 113 patients with PE, RV and LV ejection fraction (EF) and RV/LV diameter and volume ratios were associated with adverse outcome (P < .05), whereas vascular obstruction index was not. RVEF had the largest area under the receiver operating characteristic curve (0.75; 95% CI, 0.62-0.88) for predicting adverse outcome but had no significant incremental value over the RV/LV function ratio (0.72; 95% CI, 0.57-0.86; P = .25). All parameters revealed high negative predictive values (94%-98%) but low positive predictive values (13%-18%). For disease-specific outcome, areas under the curve were 0.80 (95% CI, 0.69-0.91) for RVEF vs 0.68 (95% CI, 0.48-0.88) for axial RV/LV ratio; the difference was not significant (P = .07). RVEF and RV/LV ratio proved better predictors for outcome than pulmonary obstruction index (both P < .001). CONCLUSIONS RVEF was the best predictor for clinical outcome in patients with acute PE. However, incremental value of RVEF over axial RV/LV ratio was not found.

D-dimer Testing in Patients with Suspected Pulmonary Embolism and Impaired Renal Function

BACKGROUND Determination of pretest probability and D-dimer tests are the first diagnostic steps in patients with suspected pulmonary embolism, which can be ruled out when clinical probability is unlikely and D-dimer level is normal. We evaluated the utility of D-dimer testing in patients with impaired renal function. METHODS D-dimer tests were performed in consecutive patients with suspected pulmonary embolism and an unlikely clinical probability. Creatinine levels were assessed as clinical routine. Glomerular filtration rate was calculated using the Modification of Diet in Renal Disease formula. Correlation between D-dimer level and renal function and proportions of patients with normal D-dimer in different categories of estimated glomerular filtration rate (eGFR) were assessed. Different categories of decreasing eGFR were defined as: normal renal function (eGFR >89 mL/min), mild decrease in eGFR (eGFR 60-89 mL/min), and moderate decrease in eGFR (eGFR 30-59 mL/min). RESULTS Creatinine levels were assessed in 351 of 385 patients (91%). D-dimer levels significantly increased in 3 categories of decreasing eGFR (P = .027 and P = .021 for moderate renal impairment compared with mild renal impairment and normal renal function, respectively). Normal D-dimer levels were found in 58% of patients with eGFR >89 mL/min, in 54% with eGFR 60-89 mL/min, and in 28% with eGFR 30-59 mL/min. CONCLUSIONS The specificity of D-dimer testing in patients with suspected pulmonary embolism and decreased GFR is significantly decreased. Nonetheless, performing D-dimer tests is still useful because computed tomography scanning can be withheld in a significant proportion of these patients.