Thromboembolic events, bleeding, and drug discontinuation in patients with atrial fibrillation on anticoagulation: a prospective hospital-based registry

Abstract Background The clinical practice of stroke prevention in atrial fibrillation (AF) with direct oral anticoagulants (DOACS) differs from anticoagulation in randomized trial patients. We investigated the risk of thromboembolism, bleeding, and drug discontinuation in a hospital-based real-world setting. Methods All-comer patients with non-valvular AF were recruited into a registry at an academic tertiary care center. After informed consent, patients underwent a personal structured interview including medical history, past and current anticoagulation, and returned for follow-up after 6–12 months. Results The registry comprised 282 patients (42% women, median age 71 years) with a median CHA2DS2-Vasc-Score of 4 (25. to 75. percentile 2.5–5), who were prospectively followed 285 days in median. At inclusion, 118 patients took vitamin-K-antagonists, 33 dabigatran, 87 rivaroxaban, 30 apixaban, 5 low-molecular-weight heparin, and 9 were on no anticoagulant. Occurrence of stroke (rate 2.8/100 patient-years), was associated with prior stroke (hazard ratio [HR] 18.5, 95% confidence interval 2.16–159), increased HbA1c (HR per 1% increase 1.71, 1.20–2.45) and borderline significantly associated with vascular disease (HR 8.33, 0.97–71.3). Further we observed a high rate of major bleeding (2.8/100 patient-years), clinically relevant non-major bleeding (4.1/100 patient-years), and venous thromboembolism (2.8/100 patient-years). Anticoagulation was discontinued by 80 patients (36.9/100 patient-years), and diabetes (HR 2.31, 1.32–4.02), history of bleeding (HR 2.51, 1.44–4.37) and elevated leucocyte count (HR per 1G/l increase 1.02, 1.00–1.05) were associated with increased risk of discontinuation. Conclusions In this hospital-based registry, patients with atrial fibrillation had an increased risk of thromboembolic events despite anticoagulation. The low drug persistence may be attributable to distinct comorbid conditions and bleeding complications

A new measure for in vivo thrombin activity in comparison with in vitro thrombin generation potential in patients with hyper- and hypocoagulability

The thrombin generation potential is an in vitro measure for the capacity of an individual to generate thrombin and recognized as a reflection of a hypo- or hypercoagulable status. Measurement of the in vivo thrombin activity, however, may be of clinical significance. We evaluated a new assay for in vivo thrombin activity and compared it to the in vitro thrombin generation potential in patients with hemophilia A (N = 15), oral anticoagulation for atrial fibrillation (AF) (N = 20), subjects with active cancer (N = 21), and healthy volunteers (N = 10). Thrombin activity was measured with a commercially available oligonucleotide enzyme capture assay in argatroban-stabilized plasma samples. Thrombin generation potential was determined with a commercially available assay in citrated plasma. Thrombin activity was detected in 17 (30.4 %) patients (mean 0.30 mU/ml [SD 0.80]), and in 39 patients (69.6 %) no thrombin activity was present. In cancer patients, thrombin activity was detected in 11 patients (52 %) (range 0.14-5.00 mU/ml) and was particularly increased in 3 patients with vessel-invasive tumors (1.2, 1.5, and 5.0 mU/ml). In AF patients, thrombin activity was only measureable in two patients (10 %) (recent hematoma [0.4 mU/ml] and recent ischemic stroke [1.5 mU/ml]). Thrombin activity was detected in four patients (27 %) with hemophilia (range 0.29-1.75 mU/ml), all of whom had received a factor VIII infusion on the same day. Thrombin activity did not correlate with any of the parameters of the thrombin generation potential. Only patients in acute procoagulatory states or after clotting factor replacement had elevated in vivo thrombin activity, which was, however, unrelated to the in vitro thrombin generation potential

Characterization of a prothrombotic phenotype using thrombin generation and thrombin activity in cirrhosis and portal hypertension

Background: Patients with advanced chronic liver disease (ACLD) may develop a prothrombotic phenotype that seems to be more pronounced with more severe liver dysfunction. An imbalance of endogenous pro- and anticoagulants is not fully captured by routine coagulation assays. Methods: In a cohort of ACLD patients undergoing hepatic venous pressure gradient (HVPG) measurement, we assessed thrombin generation (TGA) using two commercially available assays (Technothrombin and Thrombinoscope) with and without addition of soluble thrombomodulin (TM), as well as thrombin activity, alongside a panel of coagulation parameters. Results: The cohort encompassed 37 patients (median age 55.3 years, mean HVPG 16 ± 5 mm Hg). In the TM-modified Thrombinoscope TGA, the endogenous thrombin generation potential (ETP) was significantly increased in Child-Pugh-Score (CPS) B/C patients (N = 23, 62 %) compared to CPS A patients (N = 14, 38 %) (ETP: 546 nM∗min (443–696) vs. 404 nM∗min (289–573), p = 0.028). Using the Technothrombin TGA without TM, patients with CPS B/C had decreased ETP compared to CPS A patients (ETP: 2792 ± 1336 nM∗min vs. 5040 ± 816 nM∗min, p &lt; 0.001) and with addition of TM (final concentration: 5 nM; ETP: 2545 ± 1327 nM∗min vs. 4824 ± 929 nM∗min, p &lt; 0.001). Thrombin activity levels were 0.6pM in median (0.2–1.6pM) and above the level of detectability (0.10pM) in 94.6 % of patients but were not correlated to severity of cirrhosis (CPS A 0.7pM vs CPS B/C 0.4pM, p = 0.377) nor to parameters of TGA. Conclusion: Thrombin plasma levels are elevated in liver disease patients without apparent correlation to TGA or severity of cirrhosis. TGAs can be modified with TM to enable protein C-dependent anticoagulation, but result in differences with regard to severity of liver disease.</p

Characterization of a prothrombotic phenotype using thrombin generation and thrombin activity in cirrhosis and portal hypertension

Background: Patients with advanced chronic liver disease (ACLD) may develop a prothrombotic phenotype that seems to be more pronounced with more severe liver dysfunction. An imbalance of endogenous pro- and anticoagulants is not fully captured by routine coagulation assays. Methods: In a cohort of ACLD patients undergoing hepatic venous pressure gradient (HVPG) measurement, we assessed thrombin generation (TGA) using two commercially available assays (Technothrombin and Thrombinoscope) with and without addition of soluble thrombomodulin (TM), as well as thrombin activity, alongside a panel of coagulation parameters. Results: The cohort encompassed 37 patients (median age 55.3 years, mean HVPG 16 ± 5 mm Hg). In the TM-modified Thrombinoscope TGA, the endogenous thrombin generation potential (ETP) was significantly increased in Child-Pugh-Score (CPS) B/C patients (N = 23, 62 %) compared to CPS A patients (N = 14, 38 %) (ETP: 546 nM∗min (443–696) vs. 404 nM∗min (289–573), p = 0.028). Using the Technothrombin TGA without TM, patients with CPS B/C had decreased ETP compared to CPS A patients (ETP: 2792 ± 1336 nM∗min vs. 5040 ± 816 nM∗min, p &lt; 0.001) and with addition of TM (final concentration: 5 nM; ETP: 2545 ± 1327 nM∗min vs. 4824 ± 929 nM∗min, p &lt; 0.001). Thrombin activity levels were 0.6pM in median (0.2–1.6pM) and above the level of detectability (0.10pM) in 94.6 % of patients but were not correlated to severity of cirrhosis (CPS A 0.7pM vs CPS B/C 0.4pM, p = 0.377) nor to parameters of TGA. Conclusion: Thrombin plasma levels are elevated in liver disease patients without apparent correlation to TGA or severity of cirrhosis. TGAs can be modified with TM to enable protein C-dependent anticoagulation, but result in differences with regard to severity of liver disease.</p

Direct oral anticoagulants in clinical practice for stroke prevention in atrial fibrillation and their effect on hemostasis and fibrinolysis

Vorhofflimmern (VHF) ist die häufigste Herzrhythmusstörung in Europa und erhöht das Risiko für ischämische Schlaganfälle. Durch die prophylaktische Behandlung mit oralen Antikoagulanzien kann das Auftreten von Schlaganfällen verhindert werden, wodurch jedoch ein erhöhtes Risiko für Blutungen in Kauf genommen werden muss. Seit der Einführung einer neuen Substanzklasse, den direkten oralen Antikoagulanzien (DOAKs), hat sich die Behandlung von Patienten mit VHF fundamental verändert. Im Rahmen dieser Thesis, habe ich Fragen bezüglich des Einsatzes von DOAKs in der klinischen Praxis und dem Einfluss der DOAKs auf die Hämostase und Fibrinolyse untersucht, insbesondere da in manchen klinischen Situationen und wissenschaftlichen Fragestellungen eine Messung der Hämostasekapazität und Fibrinolyse notwendig ist. Wir haben für die Verwirklichung dieser Ziele ein Register von Patienten mit VHF geführt, die in Behandlung an einem Zentrum der tertiären Gesundheitsversorgung mit dem Titel „BioRepository of Atrial fibrillation and HeMostasiS“ (BRAHMS) waren. In dieses Register wurden Patienten mit VHF aufgenommen und beobachtet, um Informationen zur Behandlung mit oralen Antikoagulanzien zu erheben und Blutproben zu sammeln, die für verschiedene Messverfahren zur Charakterisierung der Effekte von DOAKs verwendet wurden. Die klinischen Daten des Registers ermöglichten, das prospektive Auftreten von Schlaganfällen und Blutungskomplikationen zu untersuchen. Es zeigte sich dabei, dass Patienten aus tertiärer Gesundheitsversorgung eine höhere Inzidenz von Schlaganfällen verglichen zu Daten aus der Literatur zu Patienten aus der Primärversorgung oder Patienten in randomisierten Studien haben. Weiters wurde die Therapiepersistenz der unterschiedlichen oralen Antikoagulanzien genauer analysiert. Nach 6 Monaten bekamen nur noch 76.7% der Patienten die gleiche Antikoagulationstherapie wie zum Studieneinschluss. Mit den Blutproben aus der Biobank des Registers wurden anti-Xa Tests zur Messung des Faktor Xa-Inhibitors Rivaroxaban untersucht und in einem Methodenvergleich mit der Flüssigchromatographie mit Massenspektrometrie-Kopplung Methode verglichen. Die anti-Xa Tests zeigten eine gute Korrelation zu den Plasmaspiegelbestimmungen mittels Massenspektrometrie. Zur weiteren Beurteilung des Einflusses von Antikoagulanzien auf die Hämostase und Fibrinolyse, haben wir die experimentelle „plasma clot formation and lysis“ Methode zur Untersuchung der Fibringerinnseleigeschaften verwendet und Plasmen von Patienten analysiert, die mit Vitamin-K-Antagonisten (VKA), DOAKs und niedermolekularen Heparinen (NMH) behandelt waren. Die Parameter zur Beschreibung der Fibringerinnselentstehung korrelierten mit der Konzentration von DOAKs, dem INR Wert bei VKA und dem anti-Xa Level bei NMH. Die Zeit bis zur Gerinnsel-Lyse war jedoch entgegen früherer Publikationen nicht mit den Antikoagulanzien korreliert. Nur in Gegenwart von rekombinantem Thrombomodulin war eine Korrelation zwischen Lyse-Zeit und DOAK-Plasmakonzentrationen vorhanden. Zusammenfassend ist es mir im Rahmen dieser Thesis gelungen zu zeigen, dass die Messung von Routineparametern und experimentellen Tests zum Verständnis des Effektes der DOAKs beiträgt.Atrial fibrillation (AF) is the most frequent cardiac arrhythmia in the European population. It is a major risk factor for ischemic stroke. Continuous oral anticoagulation treatment can prevent the occurrence of stroke, but comes at the price of increased risk of bleeding events. With the introduction of a new drug class, the direct oral anticoagulants (DOACs), the clinical management of patients with AF changed fundamentally. In the process of this thesis, we aimed to investigate clinical questions concerning the real-world use of DOACs and the effect of DOACs on hemostasis parameters, especially approaches to measure the effect of DOACs on hemostasis and fibrinolysis. To address these aims, we created a registry at a tertiary care hospital, entitled the BioRepository of Atrial fibrillation and HeMostasiS (BRAHMS) to recruit and observe patients with AF on treatment with anticoagulation drugs and to sample blood to investigate assays for measurement of DOACs. Using the clinical data captured from the registry, we prospectively investigated the incidence of stroke, systemic embolism, and bleeding complications. The results showed that “real-world” patients recruited in tertiary care have a higher rate of stroke and systemic embolism events and a high rate of bleeding, compared to patients in primary care cohorts and the randomized trials that led to the licensing of DOACs for stroke prevention. We were also able to address the specific problem of drug persistence. After 6 months, only 76.7% of patients persisted on their initial anticoagulation treatment. Using the blood samples collected in BRAHMS, we investigated anti-Xa assays for measuring the concentrations of the factor Xa inhibitor rivaroxaban in a method comparison to liquid chromatography tandem mass-spectrometry (LC-MS/MS). We found that anti-Xa assays are highly precise in their estimation of the concentration of rivaroxaban. I further investigated the use of an experimental assay of plasma clot formation and lysis across samples from patients on DOACs, the VKA phenprocoumon, and low-molecular-weight heparin (LMWH). The parameters of the plasma clot formation were correlated to the specific measures of anticoagulation intensity; the INR for VKA samples, the LC-MS/MS measured DOAC concentrations and the anti-Xa level for LMWH. The parameter of clot lysis time was, against previously published findings, not correlated with the specific measures of anticoagulation unless in the presence of recombinant thrombomodulin. Summarizing the key findings of projects performed within this thesis, we were able to show that despite regular monitoring being not necessary for DOAC treatment in AF, laboratory tests including routine and experimental coagulation assays are relevant for understanding the method of action of DOACs.submitted by Oliver KönigsbrüggeAbweichender Titel laut Übersetzung der Verfasserin/des VerfassersMedizinische Universität Wien, Dissertation, 2017OeBB(VLID)246758

Clinical and Experimental Medicine / Plasma clot formation and clot lysis to compare effects of different anticoagulation treatments on hemostasis in patients with atrial fibrillation

The effect of direct oral anticoagulants (DOACs) on turbidimetric measurements of plasma clot formation and susceptibility to fibrinolysis may facilitate a comparison between different classes of anticoagulants in plasma samples. We obtained 424 citrate plasma samples from 226 atrial fibrillation patients on anticoagulation and 24 samples without anticoagulation serving as controls. As comparators, we measured the international normalized ratio (INR) for phenprocoumon samples (N = 166), anti-Xa for low molecular weight heparin (LMWH) samples (N = 42), and DOAC levels with mass spectrometry (dabigatran N = 40, rivaroxaban N = 110, apixaban N = 42). Plasma clot formation and lysis were recorded continuously on a photometer after addition of an activation mix (tissue factor 2 pmol/l and tissue plasminogen activator 333 ng/ml). We used linear regression and ANCOVA for correlation analysis. Clot formation lag phase was prolonged in the presence of anticoagulants in a concentration-dependent manner for DOACs (dabigatran Spearman r = 0.74; rivaroxaban r = 0.78; apixaban r = 0.72, all p < 0.0001), INR dependent for phenprocoumon (r = 0.59, p < 0.0001), anti-Xa level dependent in LMWH samples (r = 0.90, p < 0.0001). Maximum rate of clot formation and peak clot turbidity were reduced in the presence of anticoagulants, but correlated only moderately with the comparator measures of anticoagulation. The clot lysis time was inversely correlated with DOAC concentrations in the presence of recombinant thrombomodulin. A direct ex vivo comparison between the effects of different classes of anticoagulants is possible with turbidimetric measurement of plasma clot formation and lysis. Anticoagulation inhibited clot formation in a plasma concentration manner for DOACs, INR dependent for phenprocoumon, and anti-Xa dependent for LMWH. Susceptibility to fibrinolysis increased with increasing DOAC concentrations.(VLID)359158