Large variation in anti-factor Xa levels with nadroparin as thromboprophylaxis in COVID-19 and non-COVID-19 critically ill patients.

PURPOSE: Critically ill COVID-19 and non-COVID-19 patients receive thromboprophylaxis with the LMWH nadroparin. Whether a standard dosage is adequate in attaining the target anti-FXa levels (0.20-0.50 IU/ml) in these groups is unknown. METHODS: This study was a prospective, observational study in the ICU of a large general teaching hospital in the Netherlands. COVID-19 and non-COVID-19 patients admitted to the ICU who received LMWH in a prophylactic dosage of 2850 IU, 5700 IU or 11400 IU subcutaneously were eligible for the study. Anti-FXa levels were determined 4 h after administration. Relevant laboratory parameters, prespecified co-variates and clinical data were extracted from the electronic health record system. The primary goal was to evaluate anti-FXa levels in critically ill patients on a prophylactic dosage of nadroparin. The second goal was to investigate whether covariates had an influence on anti-FXa levels. RESULTS: A total of 62 patients were included in the analysis. In the COVID-19 group and non-COVID-19 group, 29 (96%) and 12 patients (38%) reached anti-FXa levels above 0.20 IU/ml, respectively. In the non-COVID-19 group, 63% of the patients had anti-FXA levels below the target range. When adjusted for nadroparin dosage a significant relation was found between body weight and the anti-FXa level (p = 0.013). CONCLUSION: A standard nadroparin dosage of 2850 IU sc in the critically ill patient is not sufficient to attain target anti-FXa levels in the majority of the studied patient group. We suggest a standard higher dosage in combination with body-weight dependent dosing as it leads to better exposure to nadroparin. CLINICAL TRIALS REGISTRATION: Retrospectively registered, ClinicalTrials.gov ID NTC 05926518 g, date of registration 06/01/23, unique ID 2020/1725.

Cost-Effectiveness of Performing Reference Ultrasonography in Patients with Deep Vein Thrombosis.

BACKGROUND: The diagnosis of recurrent ipsilateral deep vein thrombosis (DVT) with compression ultrasonography (CUS) may be hindered by residual intravascular obstruction after previous DVT. A reference CUS, an additional ultrasound performed at anticoagulant discontinuation, may improve the diagnostic work-up of suspected recurrent ipsilateral DVT by providing baseline images for future comparison. OBJECTIVES: To evaluate the cost-effectiveness of routinely performing reference CUS in DVT patients. METHODS: Patient-level data (n = 96) from a prospective management study (Theia study; NCT02262052) and claims data were used in a decision analytic model to compare 12 scenarios for diagnostic management of suspected recurrent ipsilateral DVT. Estimated health care costs and mortality due to misdiagnosis, recurrent venous thromboembolism, and bleeding during the first year of follow-up after presentation with suspected recurrence were compared. RESULTS: All six scenarios including reference CUS had higher estimated 1-year costs (€1,763-€1,913) than the six without reference CUS (€1,192-€1,474). Costs were higher because reference CUS results often remained unused, as 20% of patients (according to claims data) would return with suspected recurrent DVT. Estimated mortality was comparable in scenarios with (14.8-17.9 per 10,000 patients) and without reference CUS (14.0-18.5 per 10,000). None of the four potentially most desirable scenarios included reference CUS. CONCLUSION: One-year health care costs of diagnostic strategies for suspected recurrent ipsilateral DVT including reference CUS are higher compared to strategies without reference CUS, without mortality benefit. These results can inform policy-makers regarding use of health care resources during follow-up after DVT. From a cost-effectiveness perspective, the findings do not support the routine application of reference CUS.

Performance of the 4-Level Pulmonary Embolism Clinical Probability Score (4PEPS) in the diagnostic management of pulmonary embolism: An external validation study.

BACKGROUND: The recently published 4-level Pulmonary Embolism Clinical Probability Score (4PEPS) integrates different aspects from currently available diagnostic strategies to further reduce imaging testing in patients with clinically suspected pulmonary embolism (PE). AIM: To externally validate the performance of 4PEPS in an independent cohort. METHODS: In this post-hoc analysis of the prospective diagnostic management YEARS study, the primary outcome measures were discrimination, calibration, efficiency (proportion of imaging tests potentially avoided), and failure rate (venous thromboembolism (VTE) diagnosis at baseline or follow-up in patients with a negative 4PEPS algorithm). Multiple imputation was used for missing 4PEPS items. Based on 4PEPS, PE was considered ruled out in patients with a very low clinical pre-test probability (CPTP) without D-dimer testing, in patients with a low CPTP and D-dimer <1000 µg/L, and in patients with a moderate CPP and D-dimer below the age-adjusted threshold. RESULTS: Of the 3465 patients, 474 (14 %) were diagnosed with VTE at baseline or during 3-month follow-up. Discriminatory performance of the 4PEPS items was good (area under ROC-curve, 0.82; 95%CI, 0.80-0.84) as was calibration. Based on 4PEPS, PE could be considered ruled out without imaging in 58 % (95%CI 57-60) of patients (efficiency), for an overall failure rate of 1.3 % (95%CI 0.86-1.9). CONCLUSION: In this retrospective external validation, 4PEPS appeared to safely rule out PE with a high efficiency. Nevertheless, although not exceeding the failure rate margin by ISTH standards, the observed failure rate in our analysis appeared to be higher than in the original 4PEPS derivation and validation study. This highlights the importance of a prospective outcome study.

Thromboembolic and bleeding complications during interruptions and after discontinuation of anticoagulant treatment in patients with atrial fibrillation and active cancer: A daily practice evaluation.

BACKGROUND AND AIMS: Cancer provides challenges to the continuity of anticoagulant treatment in patients with atrial fibrillation (AF), e.g. through cancer-related surgery or complications. We aimed to provide data on the incidence and reasons for interrupting and discontinuing anticoagulant treatment in AF patients with cancer and to assess its contribution to the risk of thromboembolism (TE) and major bleeding (MB). METHODS: This retrospective study identified AF patients with cancer in two hospitals between 2012 and 2017. Data on anticoagulant treatment, TE and MB were collected during two-year follow-up. Incidence rates (IR) per 100 patient-years and adjusted hazard ratios (aHR) were obtained for TE and MB occurring during on- and off-anticoagulant treatment, during interruption and after resumption, and after permanent discontinuation. RESULTS: 1213 AF patients with cancer were identified, of which 140 patients permanently discontinued anticoagulants and 426 patients experienced one or more interruptions. Anticoagulation was most often interrupted or discontinued due to cancer-related treatment (n = 441, 62 %), bleeding (n = 129, 18 %) or end of life (n = 36, 5 %). The risk of TE was highest off-anticoagulation and during interruptions, with IRs of 19 (14-25)) and 105 (64-13), and aHRs of 3.1 (1.9-5.0) and 4.6 (2.4-9.0), respectively. Major bleeding risk were not only increased during an interruption, but also in the first 30 days after resumption, with IRs of 33 (12-72) and 30 (17-48), and aHRs of 3.3 (1.1-9.8) and 2.4 (1.2-4.6), respectively. CONCLUSIONS: Interruption of anticoagulation therapy harbors high TE and MB risk in AF patients with cancer. The high incidence rates call for better (periprocedural) anticoagulant management strategies tailored to the cancer setting.

Atrial fibrillation in cancer: thromboembolism and bleeding in daily practice.

Background: Cancer is suggested to confer thromboembolic and bleeding risk in patients with atrial fibrillation (AF). Objectives: We aimed to describe current anticoagulant practice in patients with AF and active cancer, present incidences of thromboembolic and bleeding complications, and evaluate the association between cancer type or anticoagulant management strategy with AF-related complications. Methods: This retrospective study identified patients with AF and active cancer in 2 hospitals between January 1, 2012, and December 31, 2017. Follow-up lasted for 2 years. Data on cancer and anticoagulant treatment were collected. The outcomes of interest included ischemic stroke or transient ischemic attack (TIA) and clinically relevant nonmajor bleeding (CRNMB/MB). Incidence rates (IRs) per 100 patient-years and subdistribution hazard ratios (SHRs) with corresponding 95% Cis were estimated. Results: We identified 878 patients with AF who developed cancer (cohort 1) and 335 patients with cancer who developed AF (cohort 2). IRs for ischemic stroke/TIA and MB/CRNMB were 3.9 (2.8-5.3) and 15.7 (13.3-18.5) for cohort 1 and 4.0 (2.2-6.7) and 16.7 (12.6-21.7) for cohort 2. 14.2% (cohort 1) and 19.1% (cohort 2) of patients with a CHA2DS2-VASc score of ≥2 did not receive anticoagulant treatment. Withholding anticoagulants was associated with thromboembolic complications (SHR: 5.1 [3.20-8.0]). In nonanticoagulated patients with a CHA2DS2-VASc score of <2, IRs for stroke/TIA were 4.5 (0.75-15.0; cohort 1) and 16.0 (5.1-38.7; cohort 2). Conclusion: Patients with AF and active cancer experience high rates of thromboembolic and bleeding complications, underlying the complexity of anticoagulant management in these patients. Our data suggest that the presence of cancer is an important factor in determining the indication for anticoagulants in patients with a low CHA2DS2-VASc score.

Prior use of therapeutic anticoagulation does not protect against COVID-19 related clinical outcomes in hospitalized patients: A propensity score-matched cohort study.

The hypercoagulable state observed in COVID-19 could be responsible for morbidity and mortality. In this retrospective study we investigated whether therapeutic anticoagulation prior to infection has a beneficial effect in hospitalized COVID-19 patients. This study included 1154 COVID-19 patients admitted to 6 hospitals in the Netherlands between March and May 2020. We applied 1:3 propensity score matching to evaluate the association between prior therapeutic anticoagulation use and clinical outcome, with in hospital mortality as primary endpoint. In total, 190 (16%) patients used therapeutic anticoagulation prior to admission. In the propensity score matched analyses, we observed no associations between prior use of therapeutic anticoagulation and overall mortality (risk ratio 1.02 [95% confidence interval; 0.80-1.30]) or length of hospital stay (7.0 [4-12] vs. 7.0 [4-12] days, P = .69), although we observed a lower risk of pulmonary embolism (0.19 [0.05-0.80]). This study shows that prior use of therapeutic anticoagulation is not associated with improved clinical outcome in hospitalized COVID-19 patients.

Cost-effectiveness of magnetic resonance imaging for diagnosing recurrent ipsilateral deep vein thrombosis.

The diagnostic workup of recurrent ipsilateral deep vein thrombosis (DVT) using compression ultrasonography (CUS) can be complicated by persistent intravascular abnormalities after a previous DVT. We showed that magnetic resonance direct thrombus imaging (MRDTI) can exclude recurrent ipsilateral DVT. However, it is unknown whether the application of MRDTI in daily clinical practice is cost effective. The aim of this study was to evaluate the cost effectiveness of MRDTI-based diagnosis for suspected recurrent ipsilateral DVT during first year of treatment and follow-up in the Dutch health care setting. Patient-level data of the Theia study (NCT02262052) were analyzed in 10 diagnostic scenarios, including a clinical decision rule and D-dimer test and imaging with CUS and/or MRDTI. The total costs of diagnostic tests and treatment during 1-year follow-up, including costs of false-positive and false-negative diagnoses, were compared and related to the associated mortality. The 1-year health care costs with MRDTI (range, €1219-1296) were generally lower than strategies without MRDTI (range, €1278-1529). This was because of superior specificity, despite higher initial diagnostic costs. Diagnostic strategies including CUS alone and CUS followed by MRDTI in case of an inconclusive CUS were potential optimal cost-effective strategies, with estimated average costs of €1529 and €1263 per patient and predicted mortality of 1 per 737 patients and 1 per 609 patients, respectively. Our model shows that diagnostic strategies with MRDTI for suspected recurrent ipsilateral DVT have generally lower 1-year health care costs than strategies without MRDTI. Therefore, compared with CUS alone, applying MRDTI did not increase health care costs.

Heavy menstrual bleeding on direct factor Xa inhibitors: Rationale and design of the MEDEA study.

BACKGROUND: In premenopausal women, treatment with direct oral factor Xa inhibitors is associated with an increased risk of heavy menstrual bleeding (HMB) compared with vitamin K antagonists (VKA). Treatment with the direct oral thrombin inhibitor dabigatran appears to be associated with a reduced risk of HMB compared with VKA. These findings come from small observational studies or post hoc analyses of trials in which HMB was not a primary outcome. Use of tranexamic acid during the menstrual period may be effective in patients with HMB, but prospective data regarding efficacy and safety in patients on anticoagulant treatment are lacking. RATIONALE AND DESIGN: A direct comparison of a factor Xa inhibitor and a thrombin inhibitor with HMB as primary outcome, as well as an evaluation of the effects of adding tranexamic acid in women with anticoagulant-associated HMB is highly relevant for clinical practice. The MEDEA study is a randomized, open-label, pragmatic clinical trial to evaluate management strategies in premenopausal women with HMB associated with factor Xa inhibitor therapy. OUTCOMES: Women using factor Xa inhibitors with proven HMB, as assessed by a pictorial blood loss assessment chart (PBAC) score of >150, will be randomized to one of three study arms: (i) switch to dabigatran; (ii) continue factor Xa inhibitor with addition of tranexamic acid during the menstrual period; or (iii) continue factor Xa inhibitor without intervention. The primary outcome is the difference in PBAC score before and after randomization. Here, we present the rationale and highlight several unique features in the design of the study.

Safety of using the combination of the Wells rule and D-dimer test for excluding acute recurrent ipsilateral deep vein thrombosis.

BACKGROUND: The diagnostic accuracy of clinical probability assessment and D-dimer testing for clinically suspected recurrent deep vein thrombosis (DVT) is largely unknown. AIM: To evaluate the safety of ruling out acute recurrent DVT based on an unlikely Wells score for DVT and a normal D-dimer test. METHODS: This was a predefined endpoint of the Theia study in which the diagnostic accuracy of magnetic resonance direct thrombus imaging in acute recurrent ipsilateral DVT was validated. The Wells rule and D-dimer test, performed as part of the study protocol, were not used for management decisions. The primary outcome of this analysis was the incidence of recurrent DVT at baseline or during 3-month follow-up for patients with an unlikely Wells score and a normal D-dimer test. RESULTS: Results of both Wells score and D-dimer tests were available in 231 patients without anticoagulant treatment. The recurrent DVT prevalence was 45% (103/231). Forty-nine patients had an unlikely Wells score and normal D-dimer test, of whom 3 (6.1%, 95% confidence interval [CI] 1.3%-18%) had recurrent DVT at baseline/follow-up, yielding a sensitivity of 97% (95% CI 92%-99%) and specificity of 36% (95% CI 28%-45%). Thus, if clinical probability scoring and D-dimer testing would have been applied, radiological imaging could have been omitted in 21% of patients with a diagnostic failure rate of 6.1%. CONCLUSION: By applying clinical probability scoring and D-dimer testing, radiological imaging could be spared in one fifth of patients with suspected recurrent ipsilateral DVT. However, the high failure rate does not support implementation of this strategy in daily practice.

Magnetic resonance imaging for diagnosis of recurrent ipsilateral deep vein thrombosis.

The diagnosis of recurrent ipsilateral deep vein thrombosis (DVT) is challenging, because persistent intravascular abnormalities after previous DVT often hinder a diagnosis by compression ultrasonography. Magnetic resonance direct thrombus imaging (MRDTI), a technique without intravenous contrast and with a 10-minute acquisition time, has been shown to accurately distinguish acute recurrent DVT from chronic thrombotic remains. We have evaluated the safety of MRDTI as the sole test for excluding recurrent ipsilateral DVT. The Theia Study was a prospective, international, multicenter, diagnostic management study involving patients with clinically suspected acute recurrent ipsilateral DVT. Treatment of the patients was managed according to the result of the MRDTI, performed within 24 hours of study inclusion. The primary outcome was the 3-month incidence of venous thromboembolism (VTE) after a MRDTI negative for DVT. The secondary outcome was the interobserver agreement on the MRDTI readings. An independent committee adjudicated all end points. Three hundred five patients were included. The baseline prevalence of recurrent DVT was 38%; superficial thrombophlebitis was diagnosed in 4.6%. The primary outcome occurred in 2 of 119 (1.7%; 95% confidence interval [CI], 0.20-5.9) patients with MRDTI negative for DVT and thrombophlebitis, who were not treated with any anticoagulant during follow-up; neither of these recurrences was fatal. The incidence of recurrent VTE in all patients with MRDTI negative for DVT was 1.1% (95% CI, 0.13%-3.8%). The agreement between initial local and post hoc central reading of the MRDTI images was excellent (κ statistic, 0.91). The incidence of VTE recurrence after negative MRDTI was low, and MRDTI proved to be a feasible and reproducible diagnostic test. This trial was registered at www.clinicaltrials.gov as #NCT02262052.

Is a normal computed tomography pulmonary angiography safe to rule out acute pulmonary embolism in patients with a likely clinical probability? A patient-level meta-analysis.

A normal computed tomography pulmonary angiography (CTPA) remains a controversial criterion for ruling out acute pulmonary embolism (PE) in patients with a likely clinical probability. We set out to determine the risk of VTE and fatal PE after a normal CTPA in this patient category and compare these risk to those after a normal pulmonary angiogram of 1.7 % (95 %CI 1.0-2.7 %) and 0.3 % (95 %CI 0.02-0.7 %). A patient-level meta-analysis from 4 prospective diagnostic management studies that sequentially applied the Wells rule, D-dimer tests and CTPA to consecutive patients with clinically suspected acute PE. The primary outcome was the 3-month VTE incidence after a normal CTPA. A total of 6,148 patients were included with an overall PE prevalence of 24 %. The 3-month VTE incidence in all 4,421 patients in whom PE was excluded at baseline was 1.2 % (95 %CI 0.48-2.6) and the risk of fatal PE was 0.11 % (95 %CI 0.02-0.70). In patients with a likely clinical probability the 3-month incidences of VTE and fatal PE were 2.0 % (95 %CI 1.0-4.1 %) and 0.48 % (95 %CI 0.20-1.1 %) after a normal CTPA. The 3-month incidence of VTE was 6.3 % (95 %CI 3.0-12) in patients with a Wells rule >6 points. In conclusion, this study suggests that a normal CTPA may be considered as a valid diagnostic criterion to rule out PE in the majority of patients with a likely clinical probability, although the risk of VTE is higher in subgroups such as patients with a Wells rule >6 points for which a closer follow-up should be considered.

Simplified diagnostic management of suspected pulmonary embolism (the YEARS study): a prospective, multicentre, cohort study.

BACKGROUND: Validated diagnostic algorithms in patients with suspected pulmonary embolism are often not used correctly or only benefit subgroups of patients, leading to overuse of computed tomography pulmonary angiography (CTPA). The YEARS clinical decision rule that incorporates differential D-dimer cutoff values at presentation, has been developed to be fast, to be compatible with clinical practice, and to reduce the number of CTPA investigations in all age groups. We aimed to prospectively evaluate this novel and simplified diagnostic algorithm for suspected acute pulmonary embolism. METHODS: We did a prospective, multicentre, cohort study in 12 hospitals in the Netherlands, including consecutive patients with suspected pulmonary embolism between Oct 5, 2013, to July 9, 2015. Patients were managed by simultaneous assessment of the YEARS clinical decision rule, consisting of three items (clinical signs of deep vein thrombosis, haemoptysis, and whether pulmonary embolism is the most likely diagnosis), and D-dimer concentrations. In patients without YEARS items and D-dimer less than 1000 ng/mL, or in patients with one or more YEARS items and D-dimer less than 500 ng/mL, pulmonary embolism was considered excluded. All other patients had CTPA. The primary outcome was the number of independently adjudicated events of venous thromboembolism during 3 months of follow-up after pulmonary embolism was excluded, and the secondary outcome was the number of required CTPA compared with the Wells' diagnostic algorithm. For the primary outcome regarding the safety of the diagnostic strategy, we used a per-protocol approach. For the secondary outcome regarding the efficiency of the diagnostic strategy, we used an intention-to-diagnose approach. This trial is registered with the Netherlands Trial Registry, number NTR4193. FINDINGS: 3616 consecutive patients with clinically suspected pulmonary embolism were screened, of whom 151 (4%) were excluded. The remaining 3465 patients were assessed of whom 456 (13%) were diagnosed with pulmonary embolism at baseline. Of the 2946 patients (85%) in whom pulmonary embolism was ruled out at baseline and remained untreated, 18 patients were diagnosed with symptomatic venous thromboembolism during 3-month follow-up (0·61%, 95% CI 0·36-0·96) of whom six had fatal pulmonary embolism (0·20%, 0·07-0·44). CTPA was not indicated in 1651 (48%) patients with the YEARS algorithm compared with 1174 (34%) patients, if Wells' rule and fixed D-dimer threshold of less than 500 ng/mL would have been applied, a difference of 14% (95% CI 12-16). INTERPRETATION: In our study pulmonary embolism was safely excluded by the YEARS diagnostic algorithm in patients with suspected pulmonary embolism. The main advantage of the YEARS algorithm in our patients is the absolute 14% decrease of CTPA examinations in all ages and across several relevant subgroups. FUNDING: This study was supported by unrestricted grants from the participating hospitals.

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.

Optimization of the diagnostic management of clinically suspected pulmonary embolism in hospitalized patients.

Identical diagnostic algorithms for suspected pulmonary embolism (PE) are used for hospitalized patients and outpatients, while D-dimer levels, risk factors and pre-test probability for PE differ, and the percentage of patients managed without computerized tomography pulmonary angiography (CTPA) is lower in hospitalized patients. We aimed to improve the efficiency of the diagnostic algorithm by increasing the threshold of the D-dimer, the threshold of the Wells rule and by adjustments of the Wells rule. Six-hundred and twenty-four hospitalized patients from two previously performed management studies with a PE prevalence of 26% were studied. Adjustments were considered to be safe when the failure rate remained <2%. By applying standard management, 8% (49/624) were managed without CTPA with a failure rate of 0·0% (0/49; 95% confidence interval [CI] 0·0-7·3), and it was 1·7% (8/465; 95%CI 0·8-3·4) for all patients in whom PE was excluded at baseline. All evaluated adjustments resulted in an increase of the failure rate with very small improvements of the efficiency. Given these potentially small improvements and the increasing complexity of clinical practice if adjusted diagnostic algorithms for specific patient categories were introduced, we do not recommend further evaluation of any of the adjustments; we recommend that the standard diagnostic algorithm should continue to be applied.

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 microg/L per hour (95% CI: 0.03 to 0.13 microg/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 micromol/24 hours (95% CI: 0.01 to 0.48 micromol/24 hours; P=0.04) and 0.22 micromol/24 hours (95% CI: -0.03 to 0.46 micromol/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.

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.

Association of laboratory-defined aspirin resistance with a higher risk of recurrent cardiovascular events: a systematic review and meta-analysis.

BACKGROUND: The risk of recurrence of cardiovascular events among patients using aspirin (acetylsalicylic acid) for secondary prevention of such events remains high. Persistent platelet reactivity despite aspirin therapy, a laboratory-defined phenomenon called aspirin resistance (hereinafter, laboratory aspirin resistance), might explain this in part, but its actual contribution to the risk remains unclear. The objective of this study was to systematically review all available evidence on whether laboratory aspirin resistance is related to a higher risk of cardiovascular recurrent events. METHODS: Using a predefined search strategy, we searched electronic databases. To be included in our analysis, articles had to report on patients who used aspirin for secondary cardiovascular prevention, had to contain a clear description of a method to establish the effects of aspirin on platelet reactivity, and had to report recurrence rates of cardiovascular events. Odds ratios of cardiovascular outcome of eligible studies were pooled in a random-effects model. RESULTS: We included 15 full-text articles and 1 meeting abstract. Fifteen of these studies revealed an adverse association between laboratory aspirin resistance and occurrence of cardiovascular events. The pooled odds ratio of all cardiovascular outcomes was 3.8 (95% confidence interval, 2.3-6.1) for laboratory aspirin resistance. CONCLUSION: This systematic review and meta-analysis shows that patients biochemically identified as having laboratory aspirin resistance are more likely to also have "clinical resistance" to aspirin because they exhibit significantly higher risks of recurrent cardiovascular events compared with patients who are identified as (laboratory) aspirin sensitive.

Clopidogrel nonresponsiveness in patients undergoing percutaneous coronary intervention with stenting: a systematic review and meta-analysis.

BACKGROUND: Despite clopidogrel therapy, patients undergoing percutaneous coronary intervention (PCI) with stenting are at risk of recurrent coronary events. This could be partly explained by a reduced efficacy of clopidogrel to inhibit platelet aggregation, an ex vivo defined phenomenon called clopidogrel nonresponsiveness or resistance. However, both prevalence and associated cardiovascular risks remain unclear. We systematically reviewed evidence on prevalence and clinical consequences of laboratory clopidogrel nonresponsiveness in patients undergoing PCI. METHODS: Using predefined strategies, we searched electronic databases. To be included, articles should report on PCI patients treated with clopidogrel, contain a clear description of the method used to establish the effects of clopidogrel, and report the prevalence of clopidogrel nonresponsiveness or incidence of cardiovascular events. We analyzed prevalences with a linear mixed model that accounts for study covariates and we pooled odds ratios of clinical consequences with a random-effects model. RESULTS: We identified 25 eligible studies that included a total of 3688 patients. Mean prevalence of clopidogrel nonresponsiveness was 21% (95% CI, 17%-25%) and was inversely correlated with time between clopidogrel loading and determination of nonresponsiveness and used loading dose. The pooled odds ratio of cardiovascular outcome was 8.0 (95% CI, 3.4-19.0). CONCLUSIONS: Laboratory clopidogrel nonresponsiveness can be found in approximately 1 in 5 patients undergoing PCI. Patients ex vivo labeled nonresponsive are likely to be also "clinically nonresponsive," as they exhibit increased risks of worsened cardiovascular outcomes. Our results indicate that use of a 600-mg clopidogrel loading dose will reduce these risks, which needs to be confirmed in large prospective studies.

Prevalence of persistent platelet reactivity despite use of aspirin: a systematic review.

BACKGROUND: The absolute risk of recurrences among patients using aspirin for prevention of cardiovascular events remains high. Persistent platelet reactivity despite aspirin therapy might explain this in part. Reported prevalences of this so-called aspirin resistance vary widely, between 0% and 57%. OBJECTIVES: The aim of the study was to systematically review all available evidence on prevalence of aspirin resistance and to study determinants of reported prevalence. METHODS: Using a predefined search strategy, we searched electronic databases MEDLINE, EMBASE, CENTRAL, and Web of Science. To be included in our analysis, articles had to contain a laboratory definition of aspirin resistance, use aspirin as secondary prevention, and report associated prevalence. RESULTS: We included 34 full-text articles and 8 meeting abstracts. The mean prevalence of aspirin resistance was 24% (95% CI 20%-28%). After adjustment for differences in definition, used dosage, and population, a statistically significant higher prevalence was found in studies with aspirin dosage < or =100 mg compared with > or =300 mg (36% [95% CI 28%-43%] vs 19% [95% CI 11%-26%], P < .0001). Studies measuring platelet aggregation using light aggregometry with arachidonic acid as an agonist had a pooled unadjusted prevalence of 6% (95% CI 0%-12%). In studies using point-of-care platelet function-analyzing devices, the unadjusted prevalence was significantly higher, at 26% (95% CI 21%-31%). CONCLUSIONS: Prevalences widely differ between studies reporting on aspirin resistance. Both aspirin dosage and the method of defining aspirin resistance strongly influence estimated prevalence, which explains found heterogeneity among studies. On average, it appears that about 1 in 4 individuals may express biochemically defined aspirin resistance.