Trends in thrombolytic treatment and outcomes of acute pulmonary embolism in Germany.

AIMS: Pulmonary embolism (PE) is the third most common cardiovascular cause of death; systemic thrombolysis is potentially lifesaving treatment in patients presenting with haemodynamic instability. We investigated trends in the use of systemic thrombolysis and the outcome of patients with acute PE. METHODS AND RESULTS: We analysed data on the characteristics, comorbidities, treatment, and in-hospital outcome of 885 806 PE patients in Germany between 2005 and 2015. Incidence of acute PE was 99/100 000 population/year and increased from 85/100 000 in 2005 to 109/100 000 in 2015 [ß 0.32 (0.26-0.38), P < 0.001]. During the same period, in-hospital case fatality rates decreased from 20.4% to 13.9% [ß -0.51 (-0.52 to -0.49), P < 0.001]. The overall proportion of patients treated with systemic thrombolysis increased from 3.1% in 2005 to 4.4% in 2015 [ß 0.28 (0.25-0.31), P < 0.001]. Thrombolysis was associated with lower in-hospital mortality rates in patients with haemodynamic instability, both in those with shock not necessitating cardiopulmonary resuscitation (CPR) or mechanical ventilation [odds ratio (OR) 0.42 (0.37-0.48), P < 0.001], and in those who underwent CPR [OR 0.92 (0.87-0.97), P = 0.002]. This association was independent from age, sex, and comorbidities. However, systemic thrombolysis was administered to only 23.1% of haemodynamically unstable patients. CONCLUSION: Although the proportion of PE patients treated with systemic thrombolysis increased slightly in Germany between 2005 and 2015, only the minority of haemodynamically unstable patients currently receive this treatment. In the nationwide inpatient cohort, thrombolytic therapy was associated with reduced in-hospital mortality rates in PE patients with shock, and also in those who underwent CPR.

Monitoring of low dabigatran concentrations: diagnostic performance at clinically relevant decision thresholds.

The direct oral anticoagulant dabigatran does not require therapeutic drug monitoring, however emergency measurements are gaining importance. Current assays feature good performance at intermediate and high dabigatran concentrations but show limited accuracy at low concentrations. This area requires more attention as clinical decision threshold values currently lie at 30 and 50 ng/ml. The objective of the study was to evaluate and compare diagnostic performance of dabigatran assays at these thresholds. Dabigatran concentrations of 293 plasma samples taken from 50 patients were measured with the INNOVANCE direct thrombin inhibitor assay (DTI) from Siemens, the Biophen direct thrombin inhibitor assay (BDTI), the BDTI using a low range calibrator (BDTI-low), the Hemoclot direct thrombin inhibitor assay (HTI) and an ecarin clotting time assay (ECT). Assay results were compared to ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS), and test characteristics were calculated for thresholds of 30 and 50 ng/ml. DTI, BDTI-low and ECT showed very strong correlation and high agreement with UPLC-MS/MS and an improved determination of low dabigatran concentrations. ROC curve analyses revealed very high accuracy at the 30/50 ng/ml thresholds for DTI (AUC = 0.989/0.995), BDTI-low (AUC = 0.980/0.991) and ECT (AUC = 0.990/0.996) measurements. Sensitivity and specificity in detecting were calculated for DTI (98/92%), BDTI-low (87/95%), ECT (97/96%), BDTI (99/82%) and HTI (86/89%) measurements. Compared to the previously available HTI and BDTI, both novel assays, DTI and BDTI-low, reliably determine low dabigatran plasma concentrations around the clinical decision thresholds with very high sensitivity and specificity.

Point-of-care testing of coagulation in patients treated with edoxaban.

Edoxaban, alongside other direct oral anticoagulants (DOAC), is increasingly used for prevention of thromboembolism, including stroke. Despite DOAC therapy, however, annual stroke rate in patients with atrial fibrillation remains 1-2%. Rapid exclusion of relevant anticoagulation is necessary to guide thrombolysis or reversal therapy but, so far, no data exists on the effect of edoxaban on available point-of-care test systems (POCT). To complete our previous investigation on global coagulation-POCT for the detection of DOAC, we evaluated whether CoaguChek®-INR (CC-INR) is capable of safely ruling out edoxaban concentrations above the current treatment thresholds of 30/50 ng/mL in a blood sample. We studied patients receiving a first dose of edoxaban; excluding subjects receiving other anticoagulants. Six blood samples were collected from each patient: before drug intake, 0.5, 1, 2 and 8 h after intake, and at trough (24 h). CC-INR and mass spectrometry for edoxaban concentrations were performed for each time-point. One hundred and twenty blood samples from 20 patients contained 0-302 ng/mL of edoxaban. CC-INR ranged from 0.9 to 2.3. Pearson's correlation coefficient showed strong correlation between CC-INR and edoxaban concentrations (r = 0.73, p < 0.001). Edoxaban concentrations > 30 and > 50 ng/mL were ruled out by CC-INR ≤ 1.0 and ≤ 1.1, respectively, with high specificity (> 95%), and a sensitivity of 44% (95%-confidence interval: 30-59%) and 86% (74-93%), respectively. Our study represents the first evaluation of coagulation-POCT in edoxaban-treated patients. CC-POCT is suitable to safely exclude clinically relevant edoxaban concentrations prior to thrombolysis, or guide reversal therapy in stroke patients.

Emergency Coagulation Assessment During Treatment With Direct Oral Anticoagulants: Limitations and Solutions.

BACKGROUND AND PURPOSE: In patients receiving direct oral anticoagulants (DOACs), emergency treatment like thrombolysis for acute ischemic stroke is complicated by insufficient availability of DOAC-specific coagulation tests. Conflicting recommendations have been published concerning the use of global coagulation assays for ruling out relevant DOAC-induced anticoagulation. METHODS: Four hundred eighty-one samples from 96 DOAC-treated patients were tested using prothrombin time (PT), activated partial thromboplastin time (aPTT) and thrombin time (TT), DOAC-specific assays (anti-Xa activity, diluted TT), and liquid chromatography-tandem mass spectrometry. Sensitivity and specificity of test results to identify DOAC concentrations <30 ng/mL were calculated. Receiver operating characteristic analyses were used to define reagent-specific cutoff values. RESULTS: Normal PT and aPTT provide insufficient specificity to safely identify DOAC concentrations <30 ng/mL (rivaroxaban/PT: specificity, 77%/sensitivity, 94%; apixaban/PT: specificity, 13%/sensitivity, 94%, dabigatran/aPTT: specificity, 49%/sensitivity, 91%). Normal TT was 100% specific for dabigatran, but sensitivity was 26%. In contrast, reagent-specific PT and aPTT cutoffs provided >95% specificity and a specific TT cutoff enhanced sensitivity for dabigatran to 84%. For apixaban, no cutoffs could be established. CONCLUSIONS: Even if highly DOAC-reactive reagents are used, normal results of global coagulation tests are not suited to guide emergency treatment: whereas normal PT and aPTT lack specificity to rule out DOAC-induced anticoagulation, the low sensitivity of normal TT excludes the majority of eligible patients from treatment. However, reagent-specific cutoffs for global coagulation tests ensure high specificity and optimize sensitivity for safe emergency decision making in rivaroxaban- and dabigatran-treated patients. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifiers: NCT02371044 and NCT02371070.

Point-of-care testing for emergency assessment of coagulation in patients treated with direct oral anticoagulants.

BACKGROUND: Point-of-care testing (POCT) of coagulation has been proven to be of great value in accelerating emergency treatment. Specific POCT for direct oral anticoagulants (DOAC) is not available, but the effects of DOAC on established POCT have been described. We aimed to determine the diagnostic accuracy of Hemochron® Signature coagulation POCT to qualitatively rule out relevant concentrations of apixaban, rivaroxaban, and dabigatran in real-life patients. METHODS: We enrolled 68 patients receiving apixaban, rivaroxaban, or dabigatran and obtained blood samples at six pre-specified time points. Coagulation testing was performed using prothrombin time/international normalized ratio (PT/INR), activated partial thromboplastin time (aPTT), and activated clotting time (ACT+ and ACT-low range) POCT cards. For comparison, laboratory-based assays of diluted thrombin time (Hemoclot) and anti-Xa activity were conducted. DOAC concentrations were determined by liquid chromatography-tandem mass spectrometry. RESULTS: Four hundred and three samples were collected. POCT results of PT/INR and ACT+ correlated with both rivaroxaban and dabigatran concentrations. Insufficient correlation was found for apixaban. Rivaroxaban concentrations at <30 and <100 ng/mL were detected with >95% specificity at PT/INR POCT ≤1.0 and ≤1.1 and ACT+ POCT ≤120 and ≤130 s. Dabigatran concentrations at <30 and <50 ng/mL were detected with >95% specificity at PT/INR POCT ≤1.1 and ≤1.2 and ACT+ POCT ≤100 s. CONCLUSIONS: Hemochron® Signature POCT can be a fast and reliable alternative for guiding emergency treatment during rivaroxaban and dabigatran therapy. It allows the rapid identification of a relevant fraction of patients that can be treated immediately without the need to await the results of much slower laboratory-based coagulation tests. TRIAL REGISTRATION: Unique identifier, NCT02371070 . Retrospectively registered on 18 February 2015.

Point-of-Care Testing of Coagulation in Patients Treated With Non-Vitamin K Antagonist Oral Anticoagulants.

BACKGROUND AND PURPOSE: Specific coagulation assays for non-vitamin K antagonist oral anticoagulants (NOAC) are relatively slow and often lack availability. Although specific point-of-care tests (POCT) are currently not available, NOAC are known to affect established coagulation POCT. This study aimed at determining the diagnostic accuracy of the CoaguChek POCT to rule out relevant concentrations of rivaroxaban, apixaban, and dabigatran in real-life patients. METHODS: We consecutively enrolled 60 ischemic stroke patients newly started on NOAC treatment and obtained blood samples at 6 prespecified time points. Samples were tested using the CoaguChek POCT, laboratory-based coagulation assays (prothrombin time and activated partial thromboplastin time, anti-Xa test and Hemoclot), and liquid chromatography-tandem mass spectrometry for direct determination of NOAC concentrations. RESULTS: Three hundred fifty-six blood samples were collected. The CoaguChek POCT strongly correlated (r=0.82 P<0.001) with rivaroxaban concentrations but did not accurately detect dabigatran or apixaban. If used to estimate the presence of low rivaroxaban concentrations, POCT was superior to predictions based on normal prothrombin time and activated partial thromboplastin time values even if sensitive reagents were used. POCT-results≤1.0 predicted rivaroxaban concentrations<32 and <100 ng/mL with a specificity of 90% and 96%, respectively. CONCLUSIONS: If anti-Xa test is not available, we propose the use of the CoaguChek POCT to guide thrombolysis decisions after individual risk assessment in rivaroxaban-treated patients having acute ischemic stroke. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02371044.

A p38MAPK/MK2 signaling pathway leading to redox stress, cell death and ischemia/reperfusion injury.

BACKGROUND: Many diseases and pathological conditions are characterized by transient or constitutive overproduction of reactive oxygen species (ROS). ROS are causal for ischemia/reperfusion (IR)-associated tissue injury (IRI), a major contributor to organ dysfunction or failure. Preventing IRI with antioxidants failed in the clinic, most likely due to the difficulty to timely and efficiently target them to the site of ROS production and action. IR is also characterized by changes in the activity of intracellular signaling molecules including the stress kinase p38MAPK. While ROS can cause the activation of p38MAPK, we recently obtained in vitro evidence that p38MAPK activation is responsible for elevated mitochondrial ROS levels, thus suggesting a role for p38MAPK upstream of ROS and their damaging effects. RESULTS: Here we identified p38MAPKα as the predominantly expressed isoform in HL-1 cardiomyocytes and siRNA-mediated knockdown demonstrated the pro-oxidant role of p38MAPKα signaling. Moreover, the knockout of the p38MAPK effector MAPKAP kinase 2 (MK2) reproduced the effect of inhibiting or knocking down p38MAPK. To translate these findings into a setting closer to the clinic a stringent kidney clamping model was used. p38MAPK activity increased upon reperfusion and p38MAPK inhibition by the inhibitor BIRB796 almost completely prevented severe functional impairment caused by IR. Histological and molecular analyses showed that protection resulted from decreased redox stress and apoptotic cell death. CONCLUSIONS: These data highlight a novel and important mechanism for p38MAPK to cause IRI and suggest it as a potential therapeutic target for prevention of tissue injury.

Rapid Induction of COOLing in Stroke Patients (iCOOL1): a randomised pilot study comparing cold infusions with nasopharyngeal cooling.

INTRODUCTION: Induction methods for therapeutic cooling are under investigated. We compared the effectiveness and safety of cold infusions (CI) and nasopharyngeal cooling (NPC) for cooling induction in stroke patients. METHODS: A prospective, open-label, randomised (1:1), single-centre pilot trial with partially blinded safety endpoint assessment was conducted at the neurointensive care unit of Heidelberg University. Intubated stroke patients with an indication for therapeutic cooling and an intracranial pressure (ICP)/temperature brain probe were randomly assigned to CI (4°C, 2L at 4L/h) or NPC (60L/min for 1 h). Previous data suggested a maximum decrease of tympanic temperature for CI (2.1L within 35 min) after 52 min. Therefore the study period was 1 hour (15 min subperiods I-IV). The brain temperature course was the primary endpoint. Secondary measures included continuous monitoring of neurovital parameters and extracerebral temperatures. Statistical analysis based on repeated-measures analysis of variance. RESULTS: Of 221 patients screened, 20 were randomized within 5 months. Infusion time of 2L CI was 33 ± 4 min in 10 patients and 10 patients received NPC for 60 min. During active treatment (first 30 min), brain temperature decreased faster with CI than during NPC (I: -0.31 ± 0.2 versus -0.12 ± 0.1°C, P = 0.008; II: -1.0 ± 0.3 versus -0.49 ± 0.3°C, P = 0.001). In the CI-group, after the infusion was finished, the intervention no longer decreased brain temperature, which increased after 3.5 ± 3.3 min. Oesophageal temperature correlated best with brain temperature during CI and NPC. Tympanic temperature reacted similarly to relative changes of brain temperature during CI, but absolute values slightly differed. CI provoked three severe adverse events during subperiods II-IV (two systolic arterial pressure (SAP), one shivering) compared with four in the NPC-group, all during subperiod I (three SAP, one ICP). Classified as possibly intervention-related, two cases of ventilator failure occurred during NPC. CONCLUSIONS: In intubated stroke patients, brain cooling is faster during CI than during NPC. Importantly, contrary to previous expectations, brain cooling stopped soon after CI cessation. Oesophageal but neither bladder nor rectal temperature is suited as surrogate for brain temperature during CI and NPC. Several severe adverse events in CI and in NPC demand further studying of safety. TRIAL REGISTRATION: ClinicalTrials.gov NCT01573117. Registered 31 March 2012.

Acute Infections and Inflammatory Biomarkers in Patients with Acute Pulmonary Embolism.

Although infections are frequent in patients with pulmonary embolism (PE), its effect on adverse outcome risk remains unclear. We investigated the incidence and prognostic impact of infections requiring antibiotic treatment and of inflammatory biomarkers (C-reactive protein [CRP] and procalcitonin [PCT]) on in-hospital adverse outcomes (all-cause mortality or hemodynamic insufficiency) in 749 consecutive PE patients enrolled in a single-centre registry. Adverse outcomes occurred in 65 patients. Clinically relevant infections were observed in 46.3% of patients and there was an increased adverse outcome risk with an odds ratio (OR) of 3.12 (95% confidence interval [CI] 1.70-5.74), comparable to an increase in one risk class of the European Society of Cardiology (ESC) risk stratification algorithm (OR 3.45 [95% CI 2.24-5.30]). CRP > 124 mg/dL and PCT > 0.25 µg/L predicted patient outcome independent of other risk factors and were associated with respective ORs for an adverse outcome of 4.87 (95% CI 2.55-9.33) and 5.91 (95% CI 2.74-12.76). In conclusion, clinically relevant infections requiring antibiotic treatment were observed in almost half of patients with acute PE and carried a similar prognostic effect to an increase in one risk class of the ESC risk stratification algorithm. Furthermore, elevated levels of CRP and PCT seemed to be independent predictors of adverse outcome.

Long-term mortality in patients with pulmonary embolism: results in a single-center registry.

Background: While numerous studies have investigated short-term outcomes after pulmonary embolism (PE), long-term mortality remains insufficiently studied. Objectives: To investigate long-term outcomes in an unselected cohort of patients with PE. Methods: A total of 896 consecutive patients with PE enrolled in a single-center registry between May 2005 and December 2017 were followed up for up to 14 years. The observed mortality rate was compared with the expected rate in the general population. Results: The total follow-up time was 3908 patient-years (median, 3.1 years). The 1- and 5-year mortality rates were 19.7% (95% CI, 17.2%-22.4%) and 37.1% (95% CI, 33.6%-40.5%), respectively. The most frequent causes of death were cancer (28.5%), PE (19.4%), infections (13.9%), and cardiovascular events (11.6%). Late mortality (after >30 days) was more frequent than expected in the general population, a finding that was consistent in patients without cancer (the 5-year standardized mortality ratios were 2.77 [95% CI, 2.41-3.16] and 1.80 [95% CI, 1.50-2.14], respectively). Active cancer was the strongest risk factor for death between 30 days and 3 years (hazard ratio [HR], 6.51; 95% CI, 4.67-9.08) but was not associated with later mortality. Death after >3 years was predicted by age (HR, 1.86; 95% CI, 1.51-2.29 per decade), chronic heart failure (HR, 1.66; 95% CI, 1.02-2.70), and anemia (HR, 1.62; 95% CI, 1.09-2.41). Conclusion: The risk of mortality in patients with PE remained elevated compared with that in the general population throughout the follow-up period. The main driver of long-term mortality during the first 3 years was cancer. After that, mortality was predicted by age, chronic heart failure, and anemia.

Impact of thyroid dysfunction on short-term outcomes and long-term mortality in patients with pulmonary embolism.

BACKGROUND: A large body of evidence suggest an impact of thyroid function on outcomes of cardiovascular diseases, but results for acute pulmonary embolism (PE) are sparse. METHODS: We analysed the impact of hypothyroidism as well as hyperthyroidism on the short and long-term outcomes of patients with acute PE. The impact was compared to the group of euthyroid PE patients as reference group. RESULTS: Overall, 831 PE patients (median age 69 [IQR 56-77] years; 52.2% females) were analysed. Among these, 734 patients (88.3%) were classified as euthyroid, 40 (4.8%) as hypothyroid and 57 (6.9%) as hyperthyroid. PE patients with hypothyroidism had higher rates of adverse in-hospital outcomes (37.5% vs. 11.6%, P < 0.001), PE-related (22.5% vs. 4.8%, P < 0.001) and all-cause in-hospital death (25.0% vs. 6.8%, P < 0.001), whereas hyperthyroidism did not affect in-hospital outcomes. Long-term mortality was higher in hypothyroidism (52.5% vs. 28.9%, P = 0.002) and hyperthyroidism (43.9% vs. 28.9%, P = 0.018) compared to euthyroid function. In the 750 normotensive PE patients, hyperthyroidism affected adverse in-hospital outcome (OR 2.58 [95%CI 1.12-5.97], P = 0.026) and PE-related in-hospital mortality (OR 3.50 [95%CI 1.10-11.17], P = 0.035) in comparison to euthyroid PE patients, while hypothyroidism showed no influence. Elevated fT4 (HR 1.75 [95%CI 1.16-2.63], P = 0.007) and reduced fT3 values (HR 2.51 [95%CI 1.48-4.28], P = 0.001) were associated with increased long-term mortality. CONCLUSION: Thyroid dysfunction had a substantial impact on short and long-term outcomes of patients with acute PE. Elevated fT4 and reduced fT3 values were significantly associated with increased long-term mortality in normotensive PE patients.

Optimized definition of right ventricular dysfunction on computed tomography for risk stratification of pulmonary embolism.

OBJECTIVES: There is an ongoing discussion on the optimal right to left (RV/LV) diameter ratio threshold and the best definition of RV dysfunction on computed tomography pulmonary angiography (CTPA) for risk assessment of pulmonary embolism (PE). METHODS: On routine diagnostic CTPA, volumetric and diameter measurements (axial and reconstructed views) of the ventricles and reflux of contrast medium into the inferior vena cava (IVC) and hepatic veins were assessed in consecutive PE patients enrolled in a prospective single-center registry. In-hospital adverse outcome was defined as PE-related death, cardiopulmonary resuscitation, mechanical ventilation or catecholamine administration. RESULTS: Of 609 patients (median age, 69 [IQR, 56-77] years; 47 % male) included in the analysis, 68 patients (11.2 %) had an adverse outcome and 35 (5.7 %) died. While neither a RV/LV volume ratio ≥1.0 nor RV/LV diameter ratios ≥1.0 were able to predict an adverse outcome, higher thresholds increased specificity. Further, neither volumetric measurements nor reconstruction of images provided superior prognostic information compared to RV/LV ratios measured in axial planes. The combination of an axial RV/LV diameter ratio ≥1.5 with substantial reflux of contrast medium was present in 134 patients (22 %) and associated with the best prognostic performance to predict an adverse outcome in unselected (OR 3.7 [95 % CI, 2.0-6.6]) and normotensive (OR 2.8 [95 % CI, 1.1-6.7]) patients. CONCLUSION: A new definition of RV dysfunction (axial RV/LV diameter ratio ≥1.5 and substantial reflux of contrast medium to the IVC and hepatic veins) allows an optimized CTPA-based prediction of PE-related adverse outcome.

Outcome of patients with different clinical presentations of high-risk pulmonary embolism.

AIMS: The 2019 European Society of Cardiology (ESC) guidelines provide a revised definition of high-risk pulmonary embolism (PE) encompassing three clinical presentations: Cardiac arrest, obstructive shock, and persistent hypotension. This study investigated the prognostic implications of this new definition. METHODS AND RESULTS: Data from 784 consecutive PE patients prospectively enrolled in a single-centre registry were analysed. Study outcomes include an in-hospital adverse outcome (PE-related death or cardiopulmonary resuscitation) and in-hospital all-cause mortality. Overall, 86 patients (11.0%) presented with high-risk PE and more often had an adverse outcome (43.0%) compared to intermediate-high-risk patients (6.1%; P < 0.001). Patients with cardiac arrest had the highest rate of an in-hospital adverse outcome (78.4%) and mortality (59.5%; both P < 0.001 compared to intermediate-high-risk patients). Obstructive shock and persistent hypotension had similar rates of adverse outcomes (15.8% and 18.2%, respectively; P = 0.46), but the only obstructive shock was associated with an increased all-cause mortality risk. Use of an optimised venous lactate cut-off value (3.8 mmol/L) to diagnose obstructive shock allowed differentiation of adverse outcome risk between patients with shock (21.4%) and persistent hypotension (9.5%), resulting in a net reclassification improvement (0.24 ± 0.08; P = 0.002). CONCLUSION: The revised ESC 2019 guidelines definition of high-risk PE stratifies subgroups at different risk of in-hospital adverse outcomes and all-cause mortality. Risk prediction can be improved by using an optimised venous lactate cut-off value to diagnose obstructive shock, which might help to better assess the risk-to-benefit ratio of systemic thrombolysis in different subgroups of high-risk patients.

Specific Point-of-Care Testing of Coagulation in Patients Treated with Dabigatran.

BACKGROUND AND PURPOSE: Accurate and rapid assessment of coagulation status is necessary to guide thrombolysis or reversal of anticoagulation in stroke patients, but commercially available point-of-care (POC) assays are not suited for coagulation testing in patients treated with direct oral anticoagulants (DOACs). We aimed to evaluate the direct thrombin monitoring (DTM) test card by Helena Laboratories (Texas, United States) for anti-IIa-specific POC coagulation testing, hypothesizing that its POC-ecarin clotting time (POC-ECT) accurately reflects dabigatran plasma concentrations. METHODS: A prospective single-center diagnostic study (ClinicalTrials.gov-identifier: NCT02825394) was conducted enrolling patients receiving a first dose of dabigatran and patients already on dabigatran treatment. Blood samples were collected before drug intake and 0.5, 1, 2, 8, and 12 hours after intake. POC-ECT was performed using whole blood (WB), citrated blood (CB), and citrated plasma (CP). Dabigatran plasma concentrations were determined by mass spectrometry. RESULTS: In total, 240 blood samples from 40 patients contained 0 to 275 ng/mL of dabigatran. POC-ECT with WB/CB/CP ranged from 20 to 186/184/316 seconds. Pearson's correlation coefficient showed a strong correlation between dabigatran concentrations and POC-ECT with WB/CB/CP (R2 = 0.78/0.90/0.92). Dabigatran concentrations >30 and >50 ng/mL (thresholds for thrombolysis, surgery, and reversal therapy according to clinical guidelines) were detected by POC-ECT with WB/CB/CP (>36/35/45 and >43/45/59 seconds) with 95/97/97 and 96/98/97% sensitivity, and 81/87/94 and 74/60/91% specificity. CONCLUSION: This first study evaluating DOAC-specific POC coagulation testing revealed an excellent correlation of POC-ECT with actual dabigatran concentrations. Detecting clinically relevant dabigatran levels with high sensitivity/specificity, the DTM assay represents a suitable diagnostic tool in acute stroke, hemorrhage, and urgent surgery.

Venous lactate improves the prediction of in-hospital adverse outcomes in normotensive pulmonary embolism.

BACKGROUND: Arterial lactate is an established risk marker in patients with pulmonary embolism (PE). However, its clinical applicability is limited by the need of an arterial puncture. In contrast, venous lactate can easily be measured from blood samples obtained via routine peripheral venepuncture. METHODS: We investigated the prognostic value of venous lactate with regard to in-hospital adverse outcomes and mortality in 419 consecutive PE patients enrolled in a single-center registry between 09/2008 and 09/2017. RESULTS: An optimised venous lactate cut-off value of 3.3 mmol/l predicted both, in-hospital adverse outcome (OR 11.0 [95% CI 4.6-26.3]) and all-cause mortality (OR 3.8 [95%CI 1.3-11.3]). The established cut-off value for arterial lactate (2.0 mmol/l) and the upper limit of normal for venous lactate (2.3 mmol/l) had lower prognostic value for adverse outcomes (OR 3.6 [95% CI 1.5-8.7] and 5.7 [95% CI 2.4-13.6], respectively) and did not predict mortality. If added to the 2019 European Society of Cardiology (ESC) algorithm, venous lactate <2.3 mmol/l was associated with a high negative predictive value (0.99 [95% CI 0.97-1.00]) for adverse outcomes in intermediate-low-risk patients, whereas levels ≥3.3 mmol/l predicted adverse outcomes in the intermediate-high-risk group (OR 5.2 [95% CI 1.8-15.0]). CONCLUSION: Venous lactate above the upper limit of normal was associated with increased risk for adverse outcomes and an optimised cut-off value of 3.3 mmol/l predicted adverse outcome and mortality. Adding venous lactate to the 2019 ESC algorithm may improve risk stratification. Importantly, the established cut-off value for arterial lactate has limited specificity in venous samples and should not be used.

Point-of-care testing for emergency assessment of coagulation in patients treated with direct oral anticoagulants including edoxaban.

BACKGROUND: Direct oral anticoagulants (DOAC) including edoxaban are increasingly used for stroke prevention in atrial fibrillation. Despite treatment, annual stroke rate in these patients remains 1-2%. Rapid assessment of coagulation would be useful to guide thrombolysis or reversal therapy in this growing population of DOAC/edoxaban-treated stroke patients. Employing the Hemochron™ Signature Elite point-of-care test system (HC-POCT), clinically relevant plasma concentrations of dabigatran and rivaroxaban can be excluded in a blood sample. However, no data exists on the effect of edoxaban on HC-POCT results. We evaluated whether edoxaban plasma concentrations above the current treatment thresholds for thrombolysis or anticoagulation reversal (i.e., 30 and 50 ng/mL) can be ruled out with the HC-POCT. METHODS: We prospectively studied patients receiving a first dose of edoxaban. Six blood samples were collected from each patient: before, 0.5, 1, 2, 8, and 24 h after drug intake. HC-POCT-based INR (HC-INR), activated clotting time (HC-ACT+ and HC-ACT-LR), activated partial thromboplastin time (HC-aPTT), and mass spectrometry for edoxaban plasma concentrations were performed at each time-point. We calculated correlations, receiver operating characteristics (ROC) and test-specific cut-offs for ruling out edoxaban concentrations > 30 and > 50 ng/mL in a blood sample. RESULTS: One hundred twenty blood samples from 20 edoxaban-treated patients were analyzed. Edoxaban plasma concentrations ranged from 0 to 512 ng/mL. HC-INR/HC-ACT+/HC-ACT-LR/HC-aPTT ranged from 0.7-8.3/78-310 s/65-215 s/19-93 s, and Pearson's correlation coefficients showed moderate to very strong correlations with edoxaban concentrations (r = 0.95/0.79/0.70/0.60). With areas under the ROC curve of 0.997 (95% confidence interval: 0.991-0.971) and 0.989 (0.975-1.000), HC-INR most reliably ruled out edoxaban concentrations > 30 and > 50 ng/mL, respectively, and HC-INR results ≤1.5 and ≤ 2.1 provided specificity/sensitivity of 98.6% (91.2-99.9)/98.0% (88.0-99.9) and 96.8% (88.0-99.4)/96.5% (86.8-99.4). CONCLUSIONS: Our study represents the first systematic evaluation of the HC-POCT in edoxaban-treated patients. Applying sufficiently low assay-specific cut-offs, the HC-POCT may not only be used to reliably rule out dabigatran and rivaroxaban, but also very low edoxaban concentrations in a blood sample. Because the assay-specific cut-offs were retrospectively defined, further investigation is warranted. TRIAL REGISTRATION: ClinicalTrials.gov, registration number: NCT02825394 , registered on: 07/07/2016, URL.

Prognostic value of right atrial dilation in patients with pulmonary embolism.

AIMS: Right atrial (RA) dilation and stretch provide prognostic information in patients with cardiovascular diseases. We investigated the prevalence, confounding factors and prognostic relevance of RA dilation in patients with pulmonary embolism (PE). METHODS: Overall, 609 PE patients were consecutively included in a prospective single-centre registry between September 2008 and August 2017. Volumetric measurements of heart chambers were performed on routine non-electrocardiographic-gated computed tomography and plasma concentrations of mid-regional pro-atrial natriuretic peptide (MR-proANP) measured on admission. An in-hospital adverse outcome was defined as PE-related death, cardiopulmonary resuscitation, mechanical ventilation or catecholamine administration. RESULTS: Patients with an adverse outcome (11.2%) had larger RA volumes (median 120 (interquartile range 84-152) versus 102 (78-134) mL; p=0.013), RA/left atrial (LA) volume ratios (1.7 (1.2-2.4) versus 1.3 (1.1-1.7); p<0.001) and MR-proANP levels (282 (157-481) versus 129 (64-238) pmol·L-1; p<0.001) compared to patients with a favourable outcome. Overall, 499 patients (81.9%) had a RA/LA volume ratio ≥1.0 and a calculated cut-off value of 1.8 (area under the curve 0.64, 95% CI 0.56-0.71) predicted an adverse outcome, both in unselected (OR 3.1, 95% CI 1.9-5.2) and normotensive patients (OR 2.7, 95% CI 1.3-5.6). MR-proANP ≥120 pmol·L-1 was identified as an independent predictor of an adverse outcome, both in unselected (OR 4.6, 95% CI 2.3-9.3) and normotensive patients (OR 5.1, 95% CI 1.5-17.6). CONCLUSIONS: RA dilation is a frequent finding in patients with PE. However, the prognostic performance of RA dilation appears inferior compared to established risk stratification markers. MR-proANP predicted an in-hospital adverse outcome, both in unselected and normotensive PE patients, integrating different prognostic relevant information from comorbidities.

[Antithrombotic Treatment of Pulmonary Embolism]. / Antithrombotische Therapie bei Lungenembolie.

The present article addresses clinical challenges associated with the choice of the anticoagulant agent, the definition of the duration of anticoagulant treatment and the assessment of the risk-to-benefit ratio of prolonged anticoagulation for patients with pulmonary embolism (PE).Anticoagulation is performed with unfractionated heparin (UFH) in hemodynamically unstable patients and with low molecular weight heparins (LWMH) or fondaparinux in normotensive patients. In patients with high or intermediate clinical probability of pulmonary embolism, anticoagulation should be initiated without delay while awaiting the results of diagnostic tests. LMWH and fondaparinux are preferred over UFH in the initial anticoagulation of PE since they are associated with a lower risk of bleeding.All patients with PE require therapeutic anticoagulation for at least three months. The current 2019 guidelines of the European Society of Cardiology (ESC) recommend that all eligible patients should be treated with a non-vitamin K antagonist oral anticoagulant (NOAC) in preference to a vitamin K antagonist (VKA). In patients with active cancer, Apixaban, Edoxaban and Rivaroxaban are effective alternatives to treatment with LMWH.The decision on the duration of anticoagulation should consider both, the individual risk of PE recurrence and the individual risk of bleeding. The risk for recurrent PE after discontinuation of treatment is related to the features of the index PE event. While patients with a strong transient risk factor have a low risk of recurrence and anticoagulation can be discontinued after three months, patients with strong persistent risk factor (such as active cancer) have a high risk of recurrence and thus should receive anticoagulant treatment of indefinite duration. Given the favourable safety profile of NOACs (especially if a reduced dosage of Apixaban or Rivaroxaban is initiated after at least six months of therapeutic anticoagulation), extended oral anticoagulation of indefinite duration should be considered for all patients with intermediate risk of recurrence.

[Update diagnosis and therapeutic management of pulmonary embolism]. / Update Diagnostik und Therapie der Lungenarterienembolie.

Pulmonary embolism (PE) is a life-threatening disease and the third most frequent cardiovascular cause of death after stroke and myocardial infarction. The annual incidence is increasing. The recently published 2019 guidelines of the European Society of Cardiology integrate numerous new study findings and provide updated diagnostic and therapeutic algorithms. A standardized diagnostic approach based on clinical probability, D-dimer levels, compression sonography of the leg veins and (if necessary) CTPA should also be applied in pregnant patients with suspected PE. Assessment of right ventricular function on imaging should be part of risk stratification in every patient; the RV/LV diameter ratio can be assessed on CTPA performed for diagnosis of PE. Low risk patients are eligible for home treatment if no other reasons for hospitalization are present. Treatment decision for hemodynamically unstable patients should be made by interdisciplinary Pulmonary Embolism Response Teams. NOACs are recommended as the therapy of choice for anticoagulation of patients with PE. The duration of anticoagulation should be at least 3 months and prolonged anticoagulation should be considered for all patients without a strong triggering reversible risk factor.

Definition of tachycardia for risk stratification of pulmonary embolism.

BACKGROUND: Tachycardia is a reliable predictor of adverse outcomes in normotensive patients with acute pulmonary embolism (PE). However, different prognostic relevant heart rate thresholds have been proposed. The aim of the study was to investigate the prognostic performance of different thresholds used for defining tachycardia in normotensive PE patients. METHODS: We performed a post-hoc analysis of normotensive patients with confirmed PE consecutively included in a single-centre and a multi-centre registry. An adverse outcome was defined as PE-related death, need for mechanical ventilation, cardiopulmonary resuscitation or administration of catecholamines. RESULTS: Of 1567 patients (median age: 72 [IQR, 59-79] years; females: 46.1%) included in the analysis, 78 patients (5.0%) had an in-hospital adverse outcome. The rate of an adverse outcome was higher in patients with a heart rate ≥100 bpm (7.6%) and ≥110 bpm (8.3%) compared to patients with a heart rate <100 bpm (3.0%). A heart rate ≥100 bpm and ≥110 bpm was associated with a 2.7 (95% CI 1.7-4.3) and 2.4-fold (95% CI 1.5-3.7) increased risk for an adverse outcome, respectively. Receiver operating characteristics analysis revealed a similar area under the curve with regard to an adverse outcome for all scores and algorithm (ESC 2019 algorithm, modified FAST and Bova score) if calculated with a heart rate threshold of ≥100 bpm or of ≥110 bpm. CONCLUSIONS: Defining tachycardia by a heart rate ≥100 bpm is sufficient for risk stratification of normotensive patients with acute PE. The use of different heart rate thresholds for calculation of scores and algorithm does not appear necessary.