Diagnostic accuracy of triage tests to exclude pulmonary embolism.

We performed a study in 403 prospectively included patients with suspected pulmonary embolism to compare the accuracy of a combination of the SimpliRED D-dimer assay and an intuitive clinical probability estimate with either one alone. Based on a conjoint diagnostic refer, ence standard, including ventilation-perfusion lung scintigraphy and pulmonary angiography, the prevalence of pulmonary embolism was 31%. We demonstrated a high sensitivity (98%, 95% CI 95-100) and negative predictive value (94%, 95% CI 79-99) for the combination of the two tests. These figures were more favorable than for either test alone. The specificity of the combination was lower (11%, 95% CI 9-12) and consequently the proportion of patients in whom further diagnostic tests would have been avoided was only 8%. We conclude that the combined use of the SimpliRED test and the clinical probability estimate attains a higher sensitivity than either test alone. However, there remains a risk of false negatives and the exclusion efficiency is limited.

Increased brain natriuretic peptide as a marker for right ventricular dysfunction in acute pulmonary embolism.

Right ventricular (RV) function is of major prognostic significance in patients with acute pulmonary embolism (PE). The aim of the present study was to evaluate the role of neurohormone plasma brain natriuretic peptide (BNP) in assessing RV function in patients with acute PE. BNP levels were measured in 16 consecutive patients with acute PE as diagnosed by high probability lung scintigraphy or pulmonary angiography. Twelve healthy age-matched volunteers served as controls. All 16 patients underwent standard echocardiography and blood tests during the first hour of presentation. In the patient group, survival was studied for a period of 30 days. Plasma BNP levels in patients with acute PE were higher than in controls (7.2 [95% CI 0.4 to 144.6] versus 1.4[95% CI 0.4 to 4.6] pmol/L, p = 0.0008). Plasma BNP was significantly higher in 5 patients with RV dysfunction compared to II patients with normal RV function (40.2 [95% CI 7.5 to 214.9] versus 3.3 [95% CI 0.4 to 24.9] pmol/L, p = 0.0003). RV systolic pressure was not significantly correlated with BNP (r = 0.42, p = ns). In conclusion, plasma BNP neurohormone levels might be of clinical importance as a supplementary tool for assessment of RV function in patients with acute PE.

Use of a new monoclonal antibody-based enzyme immunoassay for soluble fibrin to exclude pulmonary embolism. ANTELOPE-Study Group.

We prospectively evaluated the diagnostic performance of a new soluble fibrin assay in 303 consecutive patients with suspected pulmonary embolism and examined potentially useful cut-off levels at which this disease can be safely excluded. In addition, the diagnostic accuracy was calculated in the subgroups of in- and outpatients. The ROC curve of the assay in the total study cohort had an area under the curve of 0.69. The cut-off level associated with a sensitivity and negative predictive value of 100% was 20 ng/ml, but the specificity was only 4%. The cut-off level with a sensitivity of 90% was 30 ng/ml, which corresponded with a specificity and negative predictive value of 27% and 86%. respectively. The diagnostic performance was comparable in the subgroups of in- and outpatients. We conclude that the soluble fibrin assay has a low diagnostic accuracy and seems unsuitable as a screening test for the exclusion of pulmonary embolism.

Comparison of a clinical probability estimate and two clinical models in patients with suspected pulmonary embolism. ANTELOPE-Study Group.

Recent studies have suggested that both the subjective judgement of a physician and standardized clinical models can be helpful in the estimation of the probability of the disease in patients with suspected pulmonary embolism (PE). We performed a multi-center study in consecutive in- and outpatients with suspected PE to compare the potential diagnostic utility of these methods. Of the 517 study patients, 160 (31%) were classified as having PE. Of these patients, 14% had a low probability as estimated by the treating physician, while 25 to 36% were categorized as having a low clinical probability with the use of two previously described clinical models. The objectively confirmed prevalence of PE in these three low probability categories was 19%, 28% and 28%, respectively. The three methods yielded comparable predictive values for PE in the other probability categories. We conclude that a physician's clinical judgement alone and two standardized clinical models, although comparable, perform disappointingly in categorizing the pre-test probability in patients with suspected PE.

Compression ultrasonography of the leg veins in patients with clinically suspected pulmonary embolism: is a more extensive assessment of compressibility useful?

We performed a multi-center study in consecutive patients with suspected pulmonary embolism to compare the diagnostic accuracy of a two-point compression ultrasonography (only the common femoral vein and popliteal vein) with an extensive examination of compressibility (from the common femoral vein until the trifurcation of calf veins). A total of 479 patients underwent the two-point compression ultrasonography. The prevalence of pulmonary embolism was 32%. The sensitivity and specificity of this procedure were 23% (95% CI 19-26) and 98% (95% CI 96-99), respectively. Extensive compression ultrasonography was performed in 461 (96%) of these 479 patients and showed comparable accuracy indices (sensitivity 25%, 95% Cl 20-28 and specificity 97%, 95% CI 95-99). We conclude that compression ultrasonography has a limited sensitivity for the detection of thrombosis in patients with acute pulmonary embolism within 24 h of presentation. A more extensive assessment of compressibility of the leg veins in these patients has no additional value as compared to the two-point assessment.

The incidence of venous thromboembolism in asymptomatic carriers of a deficiency of antithrombin, protein C, or protein S: a prospective cohort study.

Deficiencies of antithrombin, protein C, and protein S are associated with an increased risk of venous thromboembolism. The objective of this study was to prospectively assess the incidence of venous thromboembolism in nontreated asymptomatic subjects with such a deficiency. We conducted a prospective cohort study in asymptomatic family members of unselected patients who presented with a venous thromboembolic event and who were found to have a deficiency of antithrombin, protein C, or protein S. No anticoagulant prophylaxis was given to the study participants, except during risk periods for venous thromboembolism. All venous thromboembolic events were diagnosed by objective diagnostic tests. A total of 208 individuals with a mean age of 37 years (range, 15 to 79) were included in the study. A total of 611 patient observation years was obtained. Nine venous thromboembolic events occurred, resulting in an annual incidence of 1.5% (95% confidence interval [CI], 0.7 to 2.8) for the 3 deficiencies combined. Five of these events occurred spontaneously, resulting in an annual incidence of spontaneous venous thromboembolism of 0.8% (95% CI, 0.3 to 1.9). For antithrombin, protein C, and protein S deficiencies separately, this figure was 1.6%, 1.0%, and 0.4%, respectively. Thirty-four subjects experienced a total of 40 risk periods during which 4 venous thromboembolic events occurred (10% per risk period). We conclude that the use of continuous anticoagulant prophylaxis seems not warranted in asymptomatic individuals with a deficiency of antithrombin, protein C, or protein S. During risk periods for venous thromboembolism, adequate anticoagulant prophylaxis is necessary.

Safety of low-molecular-weight heparin in pregnancy: a systematic review.

Unfractionated heparin (UFH) remains the anticoagulant of choice during pregnancy. Low-molecular-weight heparins (LMWH) are an attractive alternative to UFH due to their logistic advantages and their association with a lower incidence of osteoporosis and HIT. We reviewed all published clinical reports concerning the use of LMWH during pregnancy. In addition, participants of an international interest group contributed a cohort of pregnant women treated with LMWH. Pregnancies were divided into two groups; those with and those without maternal comorbid conditions. The number of adverse fetal outcomes and the occurrence of maternal complications were evaluated in the two groups. In the group of women with comorbid conditions (n = 290), 13.4% of the pregnancies were associated with an adverse fetal outcome. In contrast, in the group of women without comorbid conditions (n = 196), 3.1% were associated with an adverse outcome, which is comparable to that seen in the normal population. We conclude that LMWH appear to be a safe alternative to unfractionated heparin as an anticoagulant during pregnancy.

Incidence of venous thromboembolism in families with inherited thrombophilia.

The risk of spontaneous or risk-period related venous thromboembolism in family members of symptomatic carriers of antithrombin (AT), protein C (PC) or protein S (PS) defects, as well as of the Factor V Leiden mutation is still undefined. We performed a retrospective cohort study in family members (n = 793) of unselected patients with a documented venous thromboembolism and one of these deficiencies to make an estimate of this risk. The annual incidences of total and spontaneous venous thromboembolic events in carriers of AT, PC or PS defects (n = 181) were 1.01% and 0.40%, respectively, as compared to 0.10% and 0.04% in non-carriers, respectively (relative risks both 10.6). In carriers of Factor V Leiden (n = 224), the annual incidences of total and spontaneous venous thromboembolism were 0.28% and 0.11%, respectively, as compared to 0.09% and 0.04% in non-carriers, respectively (relative risks 2.8 and 2.5). Additional risk factors (immobilisation, surgery and trauma: oral contraceptive use; and pregnancy/ post-partum) increased the risk of thrombosis in carriers of AT, PC and PS defects as compared to non-carriers (relative risks 8.3, 6.4 and 8.2, respectively). Oral contraceptive use and pregnancy/ post-partum period increased the risk of thrombosis in carriers of Factor V Leiden to 3.3-fold and 4.2-fold, respectively, whereas other risk factors had only a minor effect. These data lend some support to the practice of screening family members of symptomatic carriers of a AT, PC and PS deficiency. For family members of symptomatic carriers of Factor V Leiden, screening does not seem to be justified except for women in fertile age.

Is there a role for thrombolytic therapy in venous thromboembolism?

Theoretically, thrombolytic therapy would appear to offer benefits over standard heparin therapy in the treatment of venous thromboembolism based on the more rapid resolution of thrombus. In this paper, the results of clinical trials performed with thrombolytic agents in the initial treatment of both deep vein thrombosis (DVT) and pulmonary embolism (PE) are reviewed. Although there have been positive findings with surrogate markers, studies to date have failed to demonstrate that thrombolytic therapy is associated with an improved long-term clinical outcome in patients with DVT or PE. Recent reports have suggested that thrombolytic agents could be clinically useful in a subgroup who have right ventricular dysfunction on echocardiography. Randomized clinical trials, with clinically relevant endpoints, are required to determine the efficacy and safety of thrombolytic therapy in these patients.

Requirements for appropriate evaluation of diagnostic tests in suspected pulmonary embolism.

In contrast to the development of new drugs, strict guidelines for the development of new diagnostic methods do not exist. A diagnostic test can be made available without proper evaluation of its clinical utility, which can lead to its premature introduction and inappropriate use. In this review suggestions are made regarding the criteria that should be met during the various phases of development of new diagnostic techniques. It is suggested that a new diagnostic test should only be implemented in routine clinical use after all phases of development have been properly performed with good results. Several diagnostic tests for pulmonary embolism (pulmonary angiography, ventilation-perfusion scintigraphy, D-dimer assays, and spiral computed tomography), and the studies evaluating them, are thereafter reviewed. It is concluded that present pulmonary angiography and ventilation-perfusion scintigraphy are the only properly evaluated diagnostic tests for pulmonary embolism. Although new developments, such as D-dimer assays and the spiral computed tomographic scan are certainly promising, further studies are needed to determine their real value and safety in the diagnostic work-up of patients suspected of pulmonary embolism.

Recurrence of venous thromboembolism in patients with familial thrombophilia.

BACKGROUND: Treatment of patients with deep vein thrombosis and an antithrombin or protein C or S deficiency is based on case reports and personal experience. OBJECTIVE: To systematically assess the risk for recurrence of venous thromboembolism after a first episode in patients with these deficiencies, a literature review and retrospective family cohort study were performed. METHODS: For the literature review, the annual incidence of a first recurrent venous thromboembolism was assessed for each deficiency by dividing the number of venous thromboembolic events by the number of years at risk. For the family cohort study, 1- and 5-year cumulative incidences of first recurrence were calculated based on medical histories taken in relatives of consecutive patients in whom venous thromboembolism and a deficiency were diagnosed. RESULTS: For the literature review, the annual incidence of a first recurrent venous thromboembolism in patients with antithrombin or protein S deficiency ranged from 13% to 17% and 14% to 16%, respectively. For the family cohort study, the 1- and 5-year cumulative incidences of recurrent venous thromboembolism were 10% (95% confidence interval, 1%-19%) and 23% (95% confidence interval, 10%-36%), respectively. Warfarin sodium (Coumadin) prophylaxis was associated with 2 venous thromboembolic events in 141 years at risk (1.4% per year), in contrast with 19 events in 709 years at risk (2.7% per year) without prophylaxis (difference, -1.3%; 95% confidence interval, -3.5% to 1.0%). CONCLUSIONS: The annual incidence of recurrent venous thromboembolism is high during the first years following a first episode, but seems to decline thereafter. Therefore, our results challenge current practice of prescribing lifelong warfarin therapy after a first or second episode of venous thromboembolism in patients with antithrombin or protein C or S deficiency.

Frequency of pregnancy-related venous thromboembolism in anticoagulant factor-deficient women: implications for prophylaxis.

BACKGROUND: It has been reported that women with an inherited deficiency of antithrombin, protein C, or protein S have an increased risk for developing venous thromboembolic disease during pregnancy and the postpartum period. However, because the available data on risk are flawed, it is difficult to define a rational, efficacious, and safe policy about prophylaxis for venous thromboembolism in these women. OBJECTIVE: To determine the frequency of venous thromboembolism during pregnancy and the postpartum period in women with heritable deficiencies of anticoagulant factors. DESIGN: Retrospective cohort study. SETTING: University outpatient clinics in the Netherlands and Italy. PARTICIPANTS: 129 otherwise asymptomatic female family members of patients with a history of venous thromboembolism and an established deficiency of antithrombin, protein C, or protein S. MEASUREMENTS: Medical history, with specific attention to episodes of venous thromboembolism and obstetric history, was taken. The anticoagulant factor status of the study participants was determined. If a patient had an episode of venous thromboembolism, subsequent pregnancies in that patient were not analyzed. RESULTS: Of the 129 women who participated in the study, 60 had anticoagulant factor deficiency and 69 did not. In the nondeficient group, 198 pregnancies occurred; 1 of these (0.5%) was complicated by an episode of venous thromboembolism during the postpartum period. In the deficient group, 169 pregnancies occurred; 7 of these (4.1%) were complicated by an episode of venous thromboembolism during the third trimester of pregnancy (2 pregnancies [1.2%]) and the postpartum period (5 pregnancies [3.0%]). The risk for venous thromboembolism was increased eightfold in deficient women compared with nondeficient women (hazard ratio, 8.0 [95% CI 1.2 to 184]). CONCLUSIONS: Anticoagulant factor-deficient women have an increased risk for venous thromboembolism during pregnancy and the postpartum period. Although data from an appropriate randomized clinical trial are lacking, the frequency of venous thromboembolism seen in deficient women might justify the use of anticoagulative prophylaxis during the third trimester of pregnancy and the postpartum period.

The risk of abortion and stillbirth in antithrombin-, protein C-, and protein S-deficient women.

Hereditary deficiencies of the naturally occurring anticoagulants are well recognized conditions predisposing to recurrent venous thromboembolism. Since thrombotic phenomena have been implied as a cause of abortion and stillbirth, we hypothesized that these deficiencies increase the risk of fetal demise. A group of 129 female subjects who had been pregnant at least once and who had a family member with documented venous thrombosis associated with a deficiency of AT, PC or PS were studied. We first assessed the obstetric history and subsequently determined the deficiency status. In the 60 deficient subjects 42 (22.3%) of the 188 pregnancies resulted in miscarriage or stillbirth as compared to 23 (11.4%) of the 202 pregnancies in the 69 non-deficient subjects. The relative risk of abortion and stillbirth per pregnancy for deficient women as compared to non-deficient women was 2.0 (95% C.I. 1.2-3.3).