Application of Activators Ecarin and Factor Xa in Thrombelastography for Measurement of Anticoagulant Effect of Direct Oral Anticoagulants Using TEG 5000.

There are situations where monitoring direct oral anticoagulants (DOACs) would be useful, including bleedings and trauma. The thromboelastographic technique has proven useful in bleeding situations in trauma and heart surgery. The aim of this study was to examine the effect of DOACs on all currently commercially available conventional TEG®5000 assays as well as novel modified assay using Ecarin and human factor Xa (HFXa). Healthy male volunteers were given single dose of oral dabigatran 150 mg, rivaroxaban 20 mg, or apixaban 5 mg. Kaolin, RapidTEG, functional fibrinogen, PlateletMapping assay, and novel modified assays using Ecarin and HFXa were prepared. All TEG parameters were recorded. DOAC concentrations were correlated to the parameters with highest response to the DOAC effect. Sensitivity and negative predictive value of the parameter with highest response to DOAC concentration of 50 ng/mL was calculated. None of the conventional TEG assays demonstrated significant response to the effect on apixaban. Using Ecarin, reaction time R was strongly correlated with dabigatran concentrations. Using HFXa assay, R was strongly correlated with rivaroxaban and apixaban concentrations: r = 0.96, 0.84, and 0.86, respectively; p < 0.0001 for all. The R times obtained with the modified assays demonstrated strong sensitivity and negative predictive values for DOAC levels of ≥50 ng/mL. We have demonstrated that TEG®5000 can monitor the DOAC effect on hemostasis when the appropriate activator is used with significant correlation with DOAC concentrations. Larger clinical studies are warranted for correlation of TEG profile and clinical outcomes.

Measurement of Anticoagulation in Patients on Dabigatran, Rivaroxaban, and Apixaban Therapy by Novel Automated Thrombelastography.

Background Direct-acting oral anticoagulants (DOACs) do not require monitoring. Measurement of DOAC effect would be useful in the event of bleeding, trauma, and thromboembolism while on anticoagulation. We evaluated the effectiveness of the investigational DOAC assays on the TEG®6s Hemostasis Analyzer to assess the anticoagulant effect of DOACs in patients treated for atrial fibrillation or deep vein thrombosis (DVT). Methods Patients on treatment for a minimum of 7 days with standard doses of dabigatran, rivaroxaban, and apixaban were included. DOAC plasma concentrations and TEG®6s Reaction (R)-time were measured and correlated. The sensitivity, specificity, and negative predictive value (NPV) of R-time to detect DOAC concentrations of ≥30, ≥50, and ≥100 ng/mL were calculated. Results A total of 189 patients were included, ( n = 50) on apixaban, ( n = 62) on rivaroxaban, ( n = 53) on dabigatran, and ( n = 24) on no DOAC were studied. Using the direct thrombin inhibitor (DTI) channel, R-time demonstrated strong linear correlation with dabigatran levels (r = 0.93, p < 0.0001). Using the antifactor Xa (AFXa) channel, R-time demonstrated strong nonlinear correlation with rivaroxaban and apixaban levels ( r s = 0.92 and 0.84, respectively, p < 0.0001 for both). R-time revealed strong sensitivity and NPV in detecting low DOAC levels for the predefined concentrations. Conclusion R-time measured by TEG®6s DOAC-specific cartridge has a strong correlation with concentrations of the most commonly used DOACs with high sensitivity and NPV for detecting lower drug levels that are considered clinically relevant for patients in need of antidote, or prior to urgent surgery. Further studies to determine the relation of R-time to clinical outcomes are warranted.

Fully automated thromboelastograph TEG 6s to measure anticoagulant effects of direct oral anticoagulants in healthy male volunteers.

BACKGROUND: The ability to assess the hemostatic effect of the direct oral anticoagulant (DOACs) may be valuable in clinical situations such as bleeding or thrombosis, before urgent surgery, or reversal of anticoagulation. We sought to assess the anticoagulant effect of DOACs with the new-generation fully automated thrombelastograph TEG 6s using resonance-frequency viscoelasticity measurements and disposable multichannel microfluidic cartridges. METHODS: A single dose of oral dabigatran 150 mg, rivaroxaban 20 mg, or apixaban 5 mg was given to 9 healthy males. Phlebotomy was performed at 0, 1, and 3 hours after administration of DOAC. TEG parameters were measured using TEG _6s. Concentrations of DOACs were measured using chromogenic assays. The TEG parameters were correlated to the DOAC concentrations. RESULTS: The reaction time (R) demonstrated the strongest response to DOAC intake. There were no correlations between other TEG parameters and DOAC concentrations. Using the direct thrombin inhibitor (DTI) channel, R was significantly correlated with dabigatran levels (r = 0.94, P < 0.0001). Using the anti-factor Xa (AFXa) channel, R was significantly correlated with rivaroxaban and apixaban levels (r = 0.93 and r = 0.83, respectively; P < 0.0001 for both). R >2.5 minutes for dabigatran (DTI channel), >2.5 minutes for apixaban, and >1.8 minutes for rivaroxaban (AFXa channel) were associated with 100% sensitivity and ≥ 90% specificity to detect DOAC levels of ≥ 50 ng/mL. CONCLUSION: We have demonstrated that TEG _6s R has significant correlation with DOAC blood concentrations and has potential for monitoring the DOAC's effect on hemostasis with reasonable sensitivity in the small sample analyzed. This novel technology is easy to use on a small volume of whole blood without requiring a specialized laboratory. Further study is warranted to correlate R with clinical outcomes.

Rapid point-of-care detection and classification of direct-acting oral anticoagulants with the TEG 6s: Implications for trauma and acute care surgery.

BACKGROUND: The trauma patient on direct oral anticoagulant (DOAC) therapy preinjury presents a challenge in trauma and acute care surgery. Our understanding of these patients is extrapolated from vitamin K antagonists. However, DOACs have different mechanisms of action, effects on laboratory coagulation assays, and reversal strategies. Rapid identification of DOACs in the blood will allow timely reversal of factor Xa inhibitors and direct thrombin inhibitors when necessary. The present study evaluated viscoelastic testing to detect and classify DOACs in patient blood samples. METHODS: This observational, prospective, open-label, multicenter study used point-of-care viscoelastic testing to analyze blood samples taken from patients with and without DOAC treatment, and healthy volunteers. Antifactor Xa and direct thrombin inhibition (DTI) assays were used to establish reference ranges for viscoelastic testing parameters on the TEG 6s system. These ranges were applied to produce a DOAC identification algorithm for patient blood samples. Internal consistency of the measurements, as well as algorithm sensitivity and specificity, was evaluated. RESULTS: Using the TEG 6s system, the R parameter reference range was 0.6 minutes to 1.5 minutes for the Antifactor Xa assay and 1.6 minutes to 2.5 minutes for the DTI assay. Our identification algorithm using these ranges for 2.5 minutes or less has sensitives of 98.3% and 100% for factor Xa inhibitor and direct thrombin inhibitor detection, respectively. Specificity was 100%. Both classes of DOAC were detectable, even when samples were collected during the "trough" between doses of medication. CONCLUSION: Point-of-care viscoelastic testing with TEG 6s can detect and classify DOACs with high sensitivity and specificity. This tool can be used to better determine the need for reversal in trauma and acute care surgery patients and guide optimal surgical timing in the acute setting. LEVEL OF EVIDENCE: Prognostic and epidemiological study, level II.

Assessment of the effect of direct oral anticoagulants dabigatran, rivaroxaban, and apixaban in healthy male volunteers using a thrombin generation assay.

BACKGROUND: There are clinical situations where monitoring direct oral anticoagulants (DOACs) may be useful. The clinical application of thrombin generation assay (TGA) in monitoring the effect of DOACs has not been well established. An ex vivo study was performed to systematically evaluate the anticoagulant effect of dabigatran, rivaroxaban and apixaban on each individual TGA parameter through serial measurements over time to assess suitability of these parameters for monitoring the anticoagulant effect of DOACs. METHODS: Ten healthy volunteers were given oral dabigatran 150 mg, rivaroxaban 20 mg, or apixaban 10 mg once. TGA parameters lag time, endogenous Thrombin potential (ETP), and thrombin peak height, time to peak, and velocity index were measured at times 0, 2, 4, and 24 hours after intake of DOAC. TGA parameters and DOAC concentrations were correlated. RESULTS: The lag time was significantly correlated with all DOAC concentrations (r ≥ .81, P < .0001 for all). Thrombin peak height best correlated with direct Factor Xa inhibitor (FXa) concentrations in nonlinear fashion (R² ≥ .87). ETP was weakly correlated with DOAC levels (r ≤ .68). Besides lag time, the other TGA parameters were not significantly altered over time by dabigatran. CONCLUSION: Lag time was the only sensitive TGA parameter across the different classes of DOACs evaluated. Thrombin peak height was strongly correlated to FXa inhibitor concentrations and potentially a useful parameter to monitor FXa inhibitors at low concentrations. ETP had a weak correlation with achieved DOAC concentrations and is likely less suitable for assessment of DOAC effect as a stand-alone parameter.

Meta-analysis of randomized controlled trials on risk of myocardial infarction from the use of oral direct thrombin inhibitors.

Dabigatran has been associated with greater risk of myocardial infarction (MI) than warfarin. It is unknown whether the increased risk is unique to dabigatran, an adverse effect shared by other oral direct thrombin inhibitors (DTIs), or the result of a protective effect of warfarin against MI. To address these questions, we systematically searched MEDLINE and performed a meta-analysis on randomized trials that compared oral DTIs with warfarin for any indication with end point of MIs after randomization. We furthermore performed a secondary meta-analysis on atrial fibrillation stroke prevention trials with alternative anticoagulants compared with warfarin with end point of MIs after randomization. A total of 11 trials (39,357 patients) that compared warfarin to DTIs (dabigatran, ximelagatran, and AZD0837) were identified. In these trials, patients treated with oral DTIs were more likely to experience an MI than their counterparts treated with warfarin (285 of 23,333 vs 133 of 16,024, odds ratio 1.35, 95% confidence interval 1.10 to 1.66, p = 0.005). For secondary analysis, 8 studies (69,615 patients) were identified that compared warfarin with alternative anticoagulant including factor Xa inhibitors, DTIs, aspirin, and clopidogrel. There was no significant advantage in the rate of MIs with the use of warfarin versus comparators (odds ratio 1.06, 95% confidence interval 0.85 to 1.34, p = 0.59). In conclusion, our data suggest that oral DTIs were associated with increased risk of MI. This increased risk appears to be a class effect of these agents, not a specific phenomenon unique to dabigatran or protective effect of warfarin. These findings support the need for enhanced postmarket surveillance of oral DTIs and other novel agents.

Application of basic and composite thrombelastography parameters in monitoring of the antithrombotic effect of the low molecular weight heparin dalteparin: an in vivo study.

BACKGROUND: Low molecular weight heparin (LMWH) is in vast usage for treatment of thromboembolic diseases such as deep venous thrombosis and acute coronary syndromes. There are certain clinical situations where a quick point of care testing of the effect of LMWH would be useful. At this point there are no point of care devices available in the market for monitoring the effect of LMWH. Thrombelastography (TEG) evaluates the viscoelastic properties of blood during coagulation. The clinical application of TEG in monitoring LMWH treatment is not yet well defined. The purpose of this in vivo study was to systematically evaluate the most suitable TEG parameters for evaluation of the antithrombotic effect of LMWH. We furthermore evaluated for the first time the usefulness of the composite TEG parameter the Thrombodynamic Ratio (TDR) in monitoring LMWH treatment. METHODS: Healthy male volunteers (n = 7) were injected subcutaneously with the LMWH dalteparin 120 IU/kg. TEG parameters and antifactor Xa levels were measures at baseline, 2, 4, 5 and 24 hours after the injection. Correlation between TEG parameters and antiXa were calculated. The sensitivity and specificity of the TEG parameters for plasma levels of antiXa in the therapeutic range of 0.5 - 1.0 U/ml were calculated. RESULTS: All basic TEG parameters correlated significantly with antiXa levels. Among the basic parameters, the TEG reaction time R had the best correlation with antiXa levels with the most favorable combination of sensitivity and specificity for the therapeutic range of antiXa levels (r = 0.82, p < 0.0001, sensitivity 68%, specificity 100%). The composite TEG parameter TDR demonstrated the best correlation with antiXa levels, and an even more favorable combination of sensitivity and specificity compared to any of the basic parameters (r = - 0.87, p < 0.0001, sensitivity 95%, specificity 79%). CONCLUSION: The TEG reaction time R and TDR are the most suitable TEG parameters for evaluation of the antithrombotic effect of dalteparin with a highly significant correlation with antiXa levels in healthy male volunteers. Measures for uniform clinical use of these parameters are proposed. Larger clinical trials are needed to correlate R and TDR with clinical outcomes.

Left atrial volume measurement with automated border detection by 3-dimensional echocardiography: comparison with Magnetic Resonance Imaging.

OBJECTIVE: Left atrial size is an important marker for adverse cardiovascular events. There is general consensus that left atrial volume index (LAVI) is the best measurement of size. The current LAVI measurement techniques are laborious. Semi-automated measurement with a 3-dimensional echocardiography (3DE) system may be a practical clinical alternative to measure LAVI, but it has not been adequately evaluated against Magnetic Resonance Imaging (MRI) gold standard. The aim of this study was to compare the accuracy of a commercially available 3D algorithm for measurement of LAVI against LAVI obtained from MRI and Area Length Method (ALM). DESIGN: In 27 consecutive subjects referred for cardiac MRI (age 54 +/- 13 years, 63% male), LAVI was measured using 3 imaging modalities: 3DE, ALM, MRI and the results were correlated. ALM was measured using standard American Society of Echocardiography guidelines. The time required to measure LAVI by 3DE and ALM were compared. RESULTS: There was a significant correlation in systolic and diastolic LA volumes and left atrial ejection fraction between 3DE and MRI (r = 0.86 for systole, r = 0.76 for diastole, r = 0.88 for ejection fraction, P < 0.0001 for all). There was also significant correlation of diastolic volumes between 3DE and ALM (r = 0.77, P < 0.0001). The time to obtain LAVI was shorter using 3DE versus ALM (56 +/- 8 vs 135 +/- 55 seconds, P < 0.0001). CONCLUSION: Three-dimensional echocardiography with semiautomatic border detection is a practical alternative for obtaining the left atrial volume in a time-efficient manner compared to the current standard.

Analysis of 36 reported cases of late thrombosis in drug-eluting stents placed in coronary arteries.

Drug-eluting stents (DESs) have decreased the incidence of in-stent restenosis. Within the past 2 years several cases on late stent thrombosis (LST) have been reported. This study analyzed and reviewed all published cases of LST in DESs to explore possible trends not previously reported. We applied a Medline search using the key word "drug eluting stents." All 845 positive matches in March 2006 were screened for case reports of LST in DESs, defined as angiographic stent thrombosis >or=30 days after deployment. We included reported LSTs from randomized trials, observational registry reports, and letters to the editor if information regarding timing from stent deployment to clinical event, vessel, stent diameter and length, and antiplatelet regimen were available. There was no significant difference in the incidence of LST between sirolimus- and paclitaxel-eluting stents. Median time from stent deployment to clinical event was 242 days (total range 39 to 927). If aspirin and clopidogrel were discontinued, median time to clinical event was 7 days (3 to 150). In comparison, if only clopidogrel was discontinued, median time to clinical event was 30 days (14 to 690, p <0.0001). There was no significant difference in stent diameter and length between sirolimus- and paclitaxel-eluting stents. Forty-two percent of events occurred in relation to a surgical procedure for which the 2 antiplatelet agents or clopidogrel alone was discontinued. In conclusion, there was a strong association between occurrence of LST and cessation of dual antiplatelet therapy. Patients who continued on aspirin had a significant delay to the clinical event. Efforts should be made to maintain patients on aspirin during routine surgical procedures.

Alternatives to warfarin for thromboembolism prophylaxis in nonrheumatic atrial fibrillation.

Decision-making regarding thromboembolism prophylaxis in atrial fibrillation remains a major clinical challenge. While evidence of the beneficial effect of anticoagulation for patients participating in clinical trials is well established, only half of eligible individuals in the general population are currently treated with warfarin. Using an evidence-based approach, this review covers major therapeutic approaches in practice today and many of those expected to be released in the near future. Pharmacologic agents evaluated include warfarin, aspirin, other antiplatelets agents, direct thrombin inhibitors and antiarrhythmic drugs. Nonpharmacologic treatments reviewed include surgical and catheter ablation, pacing, left atrial appendage ligation and occlusion methods, and atrial defibrillators.