M. M. C. Hovens

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.

Outpatient treatment in patients with acute pulmonary embolism: the Hestia Study

Summary.  Background: Traditionally, patients with pulmonary embolism (PE) are initially treated in the hospital with low molecular weight heparin (LMWH). The results of a few small non‐randomized studies suggest that, in selected patients with proven PE, outpatient treatment is potentially feasible and safe. Objective: To evaluate the efficacy and safety of outpatient treatment according to predefined criteria in patients with acute PE. Patients and Methods: A prospective cohort study of patients with objectively proven acute PE was conducted in 12 hospitals in The Netherlands between 2008 and 2010. Patients with acute PE were triaged with the predefined criteria for eligibility for outpatient treatment, with LMWH (nadroparin) followed by vitamin K antagonists. All patients eligible for outpatient treatment were sent home either immediately or within 24 h after PE was objectively diagnosed. Outpatient treatment was evaluated with respect to recurrent venous thromboembolism (VTE), including PE or deep vein thrombosis (DVT), major hemorrhage and total mortality during 3 months of follow‐up. Results: Of 297 included patients, who all completed the follow‐up, six (2.0%; 95% confidence interval [CI] 0.8–4.3) had recurrent VTE (five PE [1.7%] and one DVT [0.3%]). Three patients (1.0%, 95% CI 0.2–2.9) died during the 3 months of follow‐up, none of fatal PE. Two patients had a major bleeding event, one of which was fatal intracranial bleeding (0.7%, 95% CI 0.08–2.4). Conclusion: Patients with PE selected for outpatient treatment with predefined criteria can be treated with anticoagulants on an outpatient basis. (Dutch Trial Register No 1319; http://www.trialregister.nl/trialreg/index.asp).

Practical Diagnostic Management of Patients with Clinically Suspected Deep Vein Thrombosis by Clinical Probability Test, Compression Ultrasonography, and D-dimer Test

PURPOSE To evaluate a new noninvasive diagnostic strategy for ruling out deep vein thrombosis consisting of either a combination of low clinical probability and normal ultrasonography or a combination of moderate-to-high clinical probability, normal ultrasonography, and a normal D-dimer test. SUBJECTS AND METHODS We studied 811 patients with clinically suspected deep vein thrombosis using a diagnostic management strategy that combined clinical probability, ultrasonography, and measurement of D-dimers. The primary endpoint was venous thromboembolism occurring during a 3-month follow-up. RESULTS Of the 280 patients (35%) with a low clinical probability, 30 (11%) had an abnormal initial ultrasonography and were treated. Of the other 250 untreated patients with low clinical probability and a normal ultrasonography, 5 (2%; 95% confidence interval [CI]: 1% to 5%) developed a nonfatal venous thromboembolism during follow-up. Of the 531 patients (65%) with a moderate-to-high clinical probability, 300 (56%) had an abnormal ultrasonography. Of the remaining 231 patients with a normal ultrasonography, 148 had a normal D-dimer test; none of these patients developed deep vein thrombosis during follow-up (0%; 95% CI: 0% to 3%). Of the 83 patients with an abnormal D-dimer test, 77 underwent repeat ultrasonography about 1 week later; none of the 64 patients with a second normal ultrasound developed symptomatic deep vein thrombosis during follow-up (0%; 95% CI: 0% to 6%). CONCLUSIONS This management strategy, which combines clinical probability, ultrasonography, and D-dimer measurements, is practical and safe in ruling out deep vein thrombosis in patients with clinically suspected thrombosis and reduces the need for repeat ultrasonography.

Aspirin in the prevention and treatment of venous thromboembolism

Summary.  This review summarizes available evidence on effects of aspirin on incidence and outcomes of venous thromboembolism (VTE). From a pathophysiological point of view, inhibition of platelet aggregation is associated with an impaired thrombus formation both in an experimental model of venous thrombosis and in vivo. Epidemiological evidence in support of a beneficial effect of acetylsalicylic acid on VTE incidence is provided by the Antiplatelet Trialists’ Collaboration meta‐analysis of studies on the use of antiplatelet agents in cardiovascular risk reduction, showing a significant 25% risk reduction of pulmonary embolism. Moreover, a meta‐analysis on older trials of antiplatelet agents in postsurgical VTE prevention and the large Pulmonary Embolism Prevention trial demonstrate a protective effect of the same magnitude: 25–30%. However, as low‐molecular‐weight heparins (LMWH) and vitamin K antagonists (VKA) have shown a superior efficacy and safety profile, and no direct comparisons have been made between aspirin, LMWH and VKA in prolonged use, the most recent guidelines advise against aspirin monotherapy for thromboprophylaxis in the surgical patient. Currently, there is no evidence to support a role for aspirin in air travel‐related VTE. Regarding prevention of recurrent VTE, studies are ongoing to determine the potential role of aspirin after a first unprovoked VTE.

Prevention of Coagulase-Negative Staphylococcal Central Venous Catheter–Related Infection Using Urokinase Rinses: A Randomized Double-Blind Controlled Trial in Patients With Hematologic Malignancies

PURPOSE Fibrin deposition at the intraluminal surface of the indwelling part of the central venous catheter (CVC) surface increases the risk of CVC-related coagulase-negative staphylococci (CoNS) infection. Therefore, repetitive enzymatic dissolution of fibrin by urokinase might reduce the risk of CVC-related infection. We undertook this study to investigate whether three times weekly urokinase rinsing of CVC reduces the incidence or severity of CVC-related infections by CoNS in patients undergoing intensive cytotoxic treatment for hematologic malignancies. PATIENTS AND METHODS In a double-blind setting, all consecutive patients with a CVC were randomly allocated to receive either urokinase rinses (5 mL of 5,000 U/mL) or placebo (saline), both three times weekly. RESULTS The percentage of patients with at least one positive culture with CoNS was lower in patients receiving urokinase compared with patients receiving placebo (26% v 42%, respectively; relative risk [RR] = 0.61; 95% CI, 0.39 to 0.94). Major CVC-related CoNS infection occurred less frequently in patients receiving urokinase versus placebo (1.2% v 14.1%, respectively; RR = 0.09; 95% CI, 0.01 to 0.50). Secondary complications, including CVC-related thrombosis, were observed less frequently in the urokinase group compared with the placebo group (1.3% v 9.0%, respectively; RR = 0.14; 95% CI, 0.02 to 0.82). No severe bleeding complications attributable to urokinase were observed. CONCLUSION Three times weekly urokinase rinsing reduces the incidence of CVC-related CoNS infection in patients treated with intensive cytotoxic therapy for hematologic malignancies, with acceptable safety.

Hestia criteria can safely select patients with pulmonary embolism for outpatient treatment irrespective of right ventricular function.

There has been debate over how patients with pulmonary embolism (PE) can be safely selected for outpatient treatment.

High D-dimer levels increase the likelihood of pulmonary embolism.

Objective.  To determine the utility of high quantitative D‐dimer levels in the diagnosis of pulmonary embolism.

Thromboembolic resolution assessed by CT pulmonary angiography after treatment for acute pulmonary embolism

The systematic assessment of residual thromboembolic obstruction after treatment for acute pulmonary embolism (PE) has been understudied. This assessment is of potential clinical importance, should clinically suspected recurrent PE occur, or as tool for risk stratification of cardiopulmonary complications or recurrent venous thromboembolism (VTE). This study aimed to assess the rate of PE resolution and its implications for clinical outcome. In this prospective, multi-center cohort study, 157 patients with acute PE diagnosed by CT pulmonary angiography (CTPA) underwent follow-up CTPA-imaging after six months of anticoagulant treatment. Two expert thoracic radiologists independently assessed the presence of residual thromboembolic obstruction. The degree of obstruction at baseline and follow-up was calculated using the Qanadli obstruction index. All patients were followed-up for 2.5 years. At baseline, the median obstruction index was 27.5 %. After six months of treatment, complete PE resolution had occurred in 84.1 % of the patients (95 % confidence interval (CI): 77.4-89.4 %). The median obstruction index of the 25 patients with residual thrombotic obstruction was 5.0 %. During follow-up, 16 (10.2 %) patients experienced recurrent VTE. The presence of residual thromboembolic obstruction was not associated with recurrent VTE (adjusted hazard ratio: 0.92; 95 % CI: 0.2-4.1).This study indicates that the incidence of residual thrombotic obstruction following treatment for PE is considerably lower than currently anticipated. These findings, combined with the absence of a correlation between residual thrombotic obstruction and recurrent VTE, do not support the routine use of follow-up CTPA-imaging in patients treated for acute PE.

Impact of delay in clinical presentation on the diagnostic management and prognosis of patients with suspected pulmonary embolism

RATIONALE The nonspecific clinical presentation of pulmonary embolism (PE) frequently leads to delay in its diagnosis. OBJECTIVES This study aimed to assess the impact of delay in presentation on the diagnostic management and clinical outcome of patients with suspected PE. METHODS In 4,044 consecutive patients with suspected PE, patients presenting more than 7 days from the onset of symptoms were contrasted with those presenting within 7 days as regards the safety of excluding PE on the basis of a clinical decision rule combined with D-dimer testing. Patients were followed for 3 months to assess the rates of recurrent venous thromboembolism and mortality. MEASUREMENTS AND MAIN RESULTS A delayed presentation (presentation >7 d) was present in 754 (18.6%) of the patients. The failure rate of an unlikely clinical probability and normal D-dimer test was 0.5% (95% confidence interval [CI], 0.01-2.7) for patients with and 0.5% (95% CI, 0.2-1.2) for those without diagnostic delay. D-dimer testing yielded a sensitivity of 99% (95% CI, 96-99%) and 98% (95% CI, 97-99%) in these groups, respectively. Patients with PE with diagnostic delay more frequently had centrally located PE (41% vs. 26%; P < 0.001). The cumulative rates of recurrent venous thromboembolism (4.6% vs. 2.7%; P = 0.14) and mortality (7.6% vs. 6.6%; P = 0.31) were not different for patients with and without delayed presentation. CONCLUSIONS PE can be safely excluded based on a clinical decision rule and D-dimer testing in patients with a delayed clinical presentation. A delayed presentation for patients who survived acute PE was associated with a more central PE location, although this did not affect the clinical outcome at 3 months.

Time-Dependent Effects of Low-Dose Aspirin on Plasma Renin Activity, Aldosterone, Cortisol, and Catecholamines

Studies have shown that aspirin may decrease blood pressure when given at bedtime but not when administered on awakening. However, until now, a biologically plausible mechanism of this striking phenomenon was not revealed. We investigated the effect of 100 mg of aspirin administered at bedtime compared with administration on awakening on plasma renin activity and aldosterone levels over 24 hours and excretion of cortisol and catecholamines in 24-hour urine samples. A randomized, placebo-controlled, double-blind, crossover trial was performed in 16 grade 1 hypertensive subjects. During 2 periods of 2 weeks separated by a 4-week washout period, participants used aspirin both at morning and at night, which was blinded with placebo. After both periods, subjects were admitted for 24 hours to measure the aforementioned parameters. Aspirin intake at bedtime compared with on awakening reduced average (24-hour) plasma renin activity by 0.08 &mgr;g/L per hour (95% CI: 0.03 to 0.13 &mgr;g/L per hour; P=0.003) without affecting aldosterone levels (95% CI: −0.01 to 0.01 nmol/L; P=0.93). Cortisol excretion in 24-hour urine was 52 nmol/24 hours (95% CI: 5 to 99 nmol/24 hours; P=0.05) lower, and dopamine and norepinephrine excretions were 0.25 &mgr;mol/24 hours (95% CI: 0.01 to 0.48 &mgr;mol/24 hours; P=0.04) and 0.22 &mgr;mol/24 hours (95% CI: −0.03 to 0.46 &mgr;mol/24 hours; P=0.02) lower in patients treated with bedtime aspirin. In conclusion, aspirin taken at bedtime compared with on awakening significantly diminished 24-hour plasma renin activity and excretion of cortisol, dopamine, and norepinephrine in 24-hour urine. Decreased activity of these pressor systems forms a biologically plausible explanation for the finding that aspirin at night may reduce blood pressure, whereas aspirin at morning does not.