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1.
Sci Rep ; 14(1): 6831, 2024 03 21.
Article in English | MEDLINE | ID: mdl-38514764

ABSTRACT

There are clinical situations where information about the anticoagulant effects of Apixaban could be useful. Specialised methods for measuring Apixaban concentrations are not available at all medical laboratories while methods for measuring the functional effects of Apixaban, using clot time ratio (CTR), can be performed in most medical laboratories around the clock using well-established measurement procedures. The aim of this study was to investigate CTR in trough and peak samples during Apixaban treatment of atrial fibrillation and to correlate the findings to bleeds and thrombotic events. Three trough- and three peak samples from 61 patients (31 on Apixaban 5 mg twice daily and 30 on Apixaban 2.5 mg twice daily) were analysed with MRX PT DOAC. Patients were followed for 30 + /-15 months, and bleeds and thrombotic events were documented. The effect of Apixaban could be measured with MRX PT DOAC and there was a statistically significant difference between CTR in trough samples compared to peak samples (p < 0.001). A total of 21 patients suffered bleeds during follow-up; two patients suffered major bleeds, and 19 suffered minor bleeds. Patients with major bleeds had both mean peak- and mean trough CTR above the respective first to third quartile (Q1-Q3) range. Four patients suffered thromboembolic events. Generally, the peak CTRs were below or in the lower end of the peak Q1-Q3 for these patients. The new test MRX PT DOAC can be used to measure the effect of Apixaban during the treatment of atrial fibrillation. High mean peak- and mean trough CTR were seen in 2 patients with major bleeds, and low peak CTR was seen in 4 patients with thromboembolic events.


Subject(s)
Atrial Fibrillation , Pyrazoles , Stroke , Thromboembolism , Thrombosis , Humans , Atrial Fibrillation/drug therapy , Atrial Fibrillation/chemically induced , Anticoagulants/adverse effects , Blood Coagulation Tests , Pyridones/adverse effects , Hemorrhage/chemically induced , Hemorrhage/drug therapy , Thrombosis/drug therapy , Thromboembolism/drug therapy , Treatment Outcome , Stroke/drug therapy , Rivaroxaban
2.
Thromb J ; 22(1): 24, 2024 Mar 01.
Article in English | MEDLINE | ID: mdl-38429728

ABSTRACT

BACKGROUND: There are situations where information about the anticoagulant effects of Rivaroxaban could be clinically useful. Methods for measuring Rivaroxaban concentrations are not available at all medical laboratories while the test MRX PT DOAC for measuring the functional effects of Rivaroxaban, in CTR (Clot Time Ratio), can be made available around the clock. The objectives of this study were to investigate CTR in trough and peak samples during Rivaroxaban treatment of atrial fibrillation and to correlate the findings to bleeding episodes. METHODS: 3 trough- and 3 peak samples from 60 patients (30 on 20 mg daily and 30 on 15 mg daily) were analyzed with PT DOAC. Patients were monitored for 20 months, and bleeding and thrombotic events were documented. Descriptive statistics were used to summarize the data and non-parametric t-test for comparison between groups. ROC curves for the prediction of DOAC plasma levels > 50 ng/mL as determined with LC-MS/MS and anti-FXa methods were computed. RESULTS: There was a significant difference between trough and peak CTR (median CTR 1.33 vs. 3.57, p < 0.001). 28 patients suffered bleeds. Patients on 20 mg Rivaroxaban with bleeds had higher mean peak CTR than patients without bleeds (CTR 4.11 vs. CTR 3.47, p = 0.040). There was no significant difference in mean CTR between patients on 15 mg Rivaroxaban with or without bleeds (CTR 3.81 vs. 3.21, p = 0.803), or when considering all patients (CTR 3.63 vs. 3.56, p = 0.445). Five out of seven patients on Rivaroxaban 20 with mean peak CTR above the dose specific first to third quartile range (Q1-Q3) suffered bleeds, while 7/16 patients with mean peak CTR within, and 1/7 patients with mean peak CTR below the Q1-Q3 suffered bleeds. The area under the ROC curve was > 0.98 at the upper limit of the PT DOAC reference interval and the negative predictive value of PT DOAC for the prediction of DOAC plasma levels > 50 ng/mL was > 0.96. CONCLUSIONS: The sample size was too low to draw any firm conclusions but is seems that MRX PT DOAC might be a useful laboratory test in situations where the effect of Rivaroxaban needs evaluation.

3.
Sci Rep ; 13(1): 9257, 2023 06 07.
Article in English | MEDLINE | ID: mdl-37286616

ABSTRACT

Guidelines do not support the combination of direct oral anticoagulants (DOACs) and the antiepileptic drug levetiracetam, due to potential relevant P-glycoprotein (P-gp) mediated interaction that might result in decreased DOACs concentrations and increased thromboembolic risk. However, there is no systematic data on the safety of this combination. The aim of this study was to find patients concurrently treated with levetiracetam and DOAC, assess their plasma concentrations of DOAC, and the incidence of thromboembolic events. From our registry of patients on anticoagulation drugs we identified 21 patients concomitantly treated with levetiracetam and DOAC, 19 patients with atrial fibrillation and two patients with venous thromboembolism. Eight patients received dabigatran, 9 apixaban and 4 rivaroxaban. For each subject blood samples were collected for determination of trough DOAC and trough levetiracetam concentrations. The average age was 75 ± 9 years, 84% were males, HAS-BLED score was 1.8 ± 0.8, and in patients with atrial fibrillation CHA2DS2-VASc score was 4.6 ± 2.0. The average trough concentration level of levetiracetam was 31.0 ± 34.5 mg/L. Median trough concentrations of DOACs were for dabigatran 72 (range 25-386) ng/mL, for rivaroxaban 47 (range 19-75) ng/mL, and for apixaban 139 (range 36-302) ng/mL. During the observation period of 1388 ± 994 days none of the patients suffered a thromboembolic event. Our results did not demonstrate a reduction in DOACs plasma levels during levetiracetam treatment, suggesting that levetiracetam could not be an important P-gp inducer in humans. DOAC in combination with levetiracetam remained effective therapy to protect against thromboembolic events.


Subject(s)
Atrial Fibrillation , Stroke , Venous Thromboembolism , Male , Humans , Aged , Aged, 80 and over , Female , Rivaroxaban , Dabigatran/adverse effects , Anticoagulants , Atrial Fibrillation/complications , Atrial Fibrillation/drug therapy , Atrial Fibrillation/epidemiology , Levetiracetam/therapeutic use , Pyridones , Venous Thromboembolism/chemically induced , Administration, Oral , Stroke/complications
4.
J Cardiovasc Dev Dis ; 9(7)2022 Jun 29.
Article in English | MEDLINE | ID: mdl-35877567

ABSTRACT

Rotational thromboelastometry (ROTEM) is a viscoelastic hemostasis test used primarily in the management of bleeding after trauma or in cardiac surgery. To allow safe and valid clinical interpretation of test results, objective specifications for analytical performance are needed, which are generally based on biological variation within (CVI) and between (CVG) individuals. The aim of this study was to evaluate biological variation in ROTEM in patients receiving rivaroxaban. Sixty patients with atrial fibrillation on stable rivaroxaban therapy were included, from whom blood was collected on six occasions: three times at trough and three at peak rivaroxaban concentrations. ROTEM® Extem and LowTF were measured as well as rivaroxaban concentration, PT, APTT, and anti-Xa. Within- (CVI) and between-subject (CVG) biological estimates were calculated. Knowledge of these biological variation components will help to establish the appropriate objective analytical performance specifications for ROTEM analysis.

5.
Biomedicines ; 9(8)2021 Jul 27.
Article in English | MEDLINE | ID: mdl-34440105

ABSTRACT

Antiphospholipid syndrome (APS) is an important cause of deep vein thrombosis (DVT). According to current APS classification criteria, APS cannot be confirmed until 24 weeks after DVT. This time frame results in frequent discontinuation of anticoagulant treatment before APS is diagnosed. Therefore, the aim of our study was to evaluate the potential predictive value of anticardiolipin (aCL) and anti-ß2glycoprotein I (anti-ß2GPI) before discontinuation of anticoagulation therapy. Patients with newly diagnosed DVT were included into a 24-month prospective study. All patients received anticoagulant therapy. aCL and anti-ß2GPI were determined at inclusion and every four weeks for the first 24 weeks and then one and two years after inclusion. APS was confirmed in 24/221 (10.9%) patients. At the time of acute DVT 20/24 (83.3%), APS patients had positive aCL and/or anti-ß2GPI. Two patients had low aCL levels and two were negative at the time of acute DVT but later met APS criteria due to lupus anticoagulant (LA). Our data indicate that negative aCL and/or anti-ß2GPI at the time of acute DVT make further aPL testing unnecessary; however, LA should be determined after discontinuation of anticoagulant therapy. Positive aCL and/or anti-ß2GPI at the time of acute DVT have a strong positive predictive value for APS and may support therapeutic decisions.

6.
Int J Cardiol ; 339: 158-163, 2021 Sep 15.
Article in English | MEDLINE | ID: mdl-34245794

ABSTRACT

BACKGROUND: Limited data are available on the role of direct oral anticoagulants (DOACs) for the treatment of upper extremities deep vein thrombosis (UEDVT). OBJECTIVES: The aim of this study was to assess the effectiveness and safety of DOACs in the treatment of UEDVT. METHODS: Patients with an objectively confirmed acute UEDVT treated with DOACs were merged from prospective cohorts to a collaborative database. Primary study outcomes were recurrent venous thromboembolism (VTE) and major bleeding occurring during DOAC treatment. RESULTS: Overall, 188 patients were included in the study: mean age 52.4 ± 20.4 years, males 43.6%, patients with active cancer 29.2%. Twenty-nine percent of patients had 2 or more risk factors for VTE, 33.0% had catheter-related or pacemaker-related UEDVT. In 13.8% of patients, DOACs were started one month after UEDVT diagnosis or later. Active cancer was an independent predictor for delayed initiation of DOACs (OR 8.1, 95% CI 3.0-22.2). Mean duration of treatment with DOACs was 5.1 ± 2.8 months. During treatment with DOACs, recurrent VTE occurred in 0.9 per 100 patient-year, major bleeding in 1.7 and all-cause deaths in 6.0 per 100 patient-year. No fatal bleeding or fatal VTE recurrence were observed. During 232.1 patient-years of follow-up after DOAC withdrawal, recurrent VTE occurred in 3.0 per 100 patient-year. The 2019 ESC categories for risk of VTE recurrences were able to discriminate patient groups at different risk of events in the on and off-treatment periods. CONCLUSIONS: Our data support the feasibility as well as the effectiveness and safety of DOACs for the treatment of acute UEDVT.


Subject(s)
Upper Extremity Deep Vein Thrombosis , Venous Thromboembolism , Administration, Oral , Adult , Aged , Anticoagulants/adverse effects , Humans , Male , Middle Aged , Prospective Studies , Upper Extremity , Upper Extremity Deep Vein Thrombosis/drug therapy , Venous Thromboembolism/drug therapy
7.
Sci Rep ; 11(1): 13908, 2021 07 06.
Article in English | MEDLINE | ID: mdl-34230559

ABSTRACT

In some clinical situations, measurements of anticoagulant effect of apixaban may be needed. We investigated the inter- and intra-individual apixaban variability in patients with atrial fibrillation and correlated these results with clinical outcome. We included 62 patients receiving either 5 mg (A5, n = 32) or 2.5 mg (A2.5, n = 30) apixaban twice-daily. We collected three trough and three peak blood samples 6-8 weeks apart. Apixaban concentration was measured by liquid chromatography-tandem mass-spectrometry (LC-MS/MS) and by anti-Xa. Patients on A2.5 were older, had lower creatinine clearance, higher CHA2DS2VASc (4.7 ± 1.0 vs. 3.4 ± 1.7) and lower trough (85 ± 39 vs. 117 ± 53 ng/mL) and peak (170 ± 56 vs. 256 ± 91 ng/mL) apixaban concentrations than patients on A5 (all p < 0.01). In patients on A5, LC-MS/MS showed a significant difference between through levels and between peak levels (p < 0.01). During apixaban treatment, 21 patients suffered bleeding (2 major). There was no association between bleeding and apixaban concentrations or variability. Four patients who suffered thromboembolic event had lower peak apixaban concentrations than patients without it (159 ± 13 vs. 238 ± 88 ng/mL, p = 0.05). We concluded, that there was a significant intra- and inter-individual variability in apixaban trough and peak concentrations. Neither variability nor apixaban concentrations were associated with clinical outcomes.


Subject(s)
Atrial Fibrillation/drug therapy , Pyrazoles/therapeutic use , Pyridones/therapeutic use , Aged , Aged, 80 and over , Atrial Fibrillation/blood , Female , Hemorrhage/chemically induced , Humans , Male , Pyrazoles/adverse effects , Pyrazoles/blood , Pyrazoles/pharmacology , Pyridones/adverse effects , Pyridones/blood , Pyridones/pharmacology , Thromboembolism/chemically induced , Treatment Outcome
8.
Sci Rep ; 11(1): 5920, 2021 03 15.
Article in English | MEDLINE | ID: mdl-33723299

ABSTRACT

Dabigatran interferes with many coagulation tests. To overcome this obstacle the use of idarucizumab as an in vitro antidote to dabigatran has been proposed. The aim of this study was to test the effect of idarucizumab as an in vitro antidote to dabigatran in ex vivo plasma samples from routine clinical patients examined by a thrombin generation assay (TGA). From 44 patients with atrial fibrillation five blood samples were collected. Thrombin generation was measured in all samples before and after the addition of idarucizumab. When idarucizumab was added to baseline plasma (no dabigatran), it caused a significantly shorter Lag Time and Time to Peak Thrombin, and a higher Peak Thrombin and Endogenous Thrombin Potential (ETP) of TGA. Similar results were obtained when idarucizumab was added to dabigatran-containing plasma, with TGA parameters comparable to baseline + idarucizumab plasma, but not to baseline plasma. In summary, our study showed that in vitro addition of idarucizumab to plasma samples from patients increases thrombin generation. The use of idarucizumab to neutralize dabigatran in patient plasma samples as well as the clinical relevance of in vitro increased thrombin generation induced by idarucizumab needs further investigation.


Subject(s)
Antibodies, Monoclonal, Humanized/pharmacology , Anticoagulant Reversal Agents/pharmacology , Blood Coagulation/drug effects , Thrombin/biosynthesis , Antithrombins/pharmacology , Blood Coagulation Tests , Dabigatran/pharmacology , Humans , Thrombin/antagonists & inhibitors
9.
Eur J Anaesthesiol ; 37(10): 874-878, 2020 10.
Article in English | MEDLINE | ID: mdl-32175987

ABSTRACT

BACKGROUND: Real-life experience with idarucizumab, which reverses the anticoagulant effect of dabigatran, is currently limited. OBJECTIVE: To evaluate efficacy and safety of the clinical use of idarucizumab after its availability in Slovenia. METHODS: We analysed consecutive cases treated with idarucizumab in Slovenia from January to October 2016. The decision to reverse dabigatran with idarucizumab was made by the treating clinicians, as was the assessment of clinical outcomes and blood sampling/monitoring (activated partial thromboplastin time, thrombin time and diluted thrombin time) before and after use. RESULTS: Idarucizumab was used in 17 cases. One patient was treated with the antidote twice with an interval of 2 months between treatments. The indications for idarucizumab use were: emergency surgery (4/17), severe bleeding (11/17; seven with intracranial bleeding) and ischaemic stroke (2/17). During surgery, no excessive bleeding was reported. Five patients died due to cardiogenic, haemorrhagic or septic shock, intracranial bleeding or multiple organ failure. Among cases with laboratory data available, baseline coagulation tests were prolonged in 12/13 cases with bleeding or emergency surgery. After idarucizumab administration, normal coagulation parameters were confirmed in 10/11. However, re-occurrence of dabigatran effect was noted later in four patients with creatinine clearance less than 30 ml min, and one patient with persistent bleeding required retreatment with idarucizumab. CONCLUSION: Our first experiences with idarucizumab use in daily-care settings support a rapid and efficient decrease in the anticoagulant effect of dabigatran in emergency situations. Late re-occurrence of dabigatran effect was noted in a subset of patients with severe renal failure.


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Brain Ischemia , Stroke , Dabigatran/adverse effects , Humans
10.
Int J Clin Pharm ; 42(2): 445-452, 2020 Apr.
Article in English | MEDLINE | ID: mdl-32170590

ABSTRACT

Background The efficacy and safety of direct oral anticoagulants is well established in patients with atrial fibrillation. However, data on their use in the oldest old patients (≥ 85 years), who have the highest risk of bleeding, is scarce. Objective The aim of this study was to evaluate the safety of direct oral anticoagulants in the oldest old patients with atrial fibrillation and assess the impact of age on major bleeding events. Setting Anticoagulation Clinic of the Department of Vascular Diseases, University Medical Centre Ljubljana, Slovenia. Methods From our single-centre prospective registry we enrolled 2260 consecutive atrial fibrillation patients aged ≥ 65 years that were started on dabigatran, rivaroxaban or apixaban. The mean duration of treatment exposure was 735 days. The primary outcome was the incidence of major bleeding. The incidence of thromboembolic events and death were also assessed. Potential risk factors for major bleeding were evaluated using Cox regression analysis. Main outcome measure Rate of major bleeding. Results During the follow-up 106 patients experienced major bleeding (2.3%/year). The oldest old patients (≥ 85 years) had the highest risk of any major bleeding (HR 2.50, 95% CI 1.44-4.32, p = 0.001), intracranial bleeding (HR 4.74, 95% CI 1.48-15.14, p < 0.01) and major gastrointestinal bleeding (HR 2.32, 95% CI 1.10-4.89, p < 0.03) compared to the group of patients aged 65-74 years, even though the majority of them were treated with reduced doses of direct oral anticoagulants. Significant predictors for major bleeding were age group ≥ 85 years (HR 2.52, 95% CI 1.43-4.47, p = 0.001) and history of bleeding (HR 3.32, 95% CI 1.87-5.90, p < 0.001). The incidence of a composite of stroke, transient ischemic attack and systemic embolism was 1.3%/year. Conclusion In this prospective real-world clinical study we have shown that the oldest old patients have the highest risk of major bleeding, which is further increased with a patient's history of bleeding.


Subject(s)
Anticoagulants/adverse effects , Factor Xa Inhibitors/adverse effects , Hemorrhage/chemically induced , Age Factors , Aged , Aged, 80 and over , Anticoagulants/therapeutic use , Atrial Fibrillation/drug therapy , Comorbidity , Dose-Response Relationship, Drug , Embolism/epidemiology , Embolism/prevention & control , Female , Health Status , Humans , Ischemic Attack, Transient/epidemiology , Ischemic Attack, Transient/prevention & control , Male , Memory, Episodic , Slovenia/epidemiology , Socioeconomic Factors , Stroke/epidemiology , Stroke/prevention & control
11.
Eur J Clin Pharmacol ; 75(8): 1069-1075, 2019 Aug.
Article in English | MEDLINE | ID: mdl-31139866

ABSTRACT

BACKGROUND: Routine laboratory monitoring of rivaroxaban and dose adjustment relating to exposure is currently not recommended. However, in certain clinical situations, assessment of rivaroxaban levels is desirable. OBJECTIVES: To examine inter- and intra-subject plasma rivaroxaban variability in patients with atrial fibrillation (AF) and to correlate these results to clinical outcomes. PATIENTS/METHODS: We included 60 patients with AF treated with rivaroxaban: half on 20 mg daily (R20) and half on 15 mg daily (R15). Three trough and peak blood samples were collected with an interval of 6-8 weeks apart. Plasma rivaroxaban concentration was measured directly by liquid chromatography-tandem mass-spectrometry (LC-MS/MS) and indirectly by anti-Xa for rivaroxaban, prothrombin time (PT), and activated partial thromboplastin time (APTT). RESULTS: Patients on R15 were older (76 ± 6 vs 71 ± 6 years), had lower creatinine clearance (60 ± 26 vs 99 ± 32 mL/min), higher CHADS2 (2.5 ± 1.2 vs 1.8 ± 1.3), all p < 0.01, but had similar rivaroxaban concentrations in trough samples to patients on R20. There was no significant intra-individual variability for trough or peak rivaroxaban concentration assessed by LC-MS/MS, anti-Xa, or PT. Trough rivaroxaban levels determined by LC-MS/MS (48 ± 30 vs 34 ± 26, p = 0.02) and anti-Xa, but not with PT and APTT, were higher in patients with bleeding than in patients without it. CONCLUSIONS: There is a pronounced inter-, but not intra-individual variability in the rivaroxaban trough levels in patients with AF. Assessment of trough rivaroxaban concentration with LC-MS/MS or anti-Xa, but not with APTT or PT, may help to identify patients at increased risk of bleeding.


Subject(s)
Atrial Fibrillation/drug therapy , Biological Variation, Individual , Biological Variation, Population , Factor Xa Inhibitors/pharmacology , Hemorrhage/epidemiology , Rivaroxaban/pharmacology , Aged , Aged, 80 and over , Blood Coagulation Tests/statistics & numerical data , Dose-Response Relationship, Drug , Drug Monitoring/statistics & numerical data , Factor Xa Inhibitors/therapeutic use , Female , Hemorrhage/chemically induced , Humans , Male , Risk Assessment , Rivaroxaban/therapeutic use
14.
Semin Thromb Hemost ; 43(1): 24-29, 2017 Feb.
Article in English | MEDLINE | ID: mdl-27336690

ABSTRACT

Asymptomatic pulmonary embolism (PE) is present in at least one-third of patients with deep venous thrombosis (DVT). However, knowledge about its influence on the prognosis of patients is limited. The aim of this study was to assess the prognostic impact of asymptomatic PE in patients with DVT and to explore risk factors for recurrent venous thromboembolic events. A total of 200 consecutive patients with the first episode of objectively confirmed DVT without symptoms of PE were included. All patients underwent ventilation-perfusion scintigraphy within 48 hours of DVT confirmation. Patients with inconclusive scans further underwent computed tomography pulmonary angiography. At the time of inclusion and 4 weeks after discontinuation of anticoagulation, the levels of biomarkers of hemostasis and inflammation were assessed. Patients were followed up for a mean period of 4.2 ± 0.6 years. Recurrent episodes of venous thromboembolisms were recorded. Consistent with the literature, asymptomatic PE was present in 33.5% of the patients. During follow-up, 27 recurrent venous thromboembolisms were recorded, 20 presenting as DVT and 7 as symptomatic PE. Asymptomatic PE wasn't significantly associated with the rate of recurrence (p = 0.676). Recurrent events were associated with unprovoked versus provoked DVT (hazard ratio [HR]: 5.01; 95% confidence interval [CI]: 2.25-11.17; p < 0.001) and with increased versus normal D-dimer values, measured 4 weeks after discontinuation of anticoagulation (HR: 6.47; 95% CI: 2.96-14.17; p < 0.001).


Subject(s)
Pulmonary Embolism/complications , Venous Thrombosis/drug therapy , Female , Humans , Male , Middle Aged , Prognosis , Pulmonary Embolism/drug therapy , Risk Factors
15.
PLoS One ; 11(6): e0156943, 2016.
Article in English | MEDLINE | ID: mdl-27280704

ABSTRACT

BACKGROUND AND AIM: Interruption of anticoagulant treatment with warfarin or non-vitamin K antagonist oral anticoagulants (NOAC) represents a vulnerable period with an increased risk of thromboembolic events. What is the incidence of thromboembolic events in real-life patients with non-valvular atrial fibrillation treated with NOAC who had a discontinuation or cessation of treatment in comparison to patients on continuous treatment? PATIENTS AND METHODS: Registry data from 866 patients with non-valvular atrial fibrillation, aged 74.3 (SD 9.8) years, with an average CHADS2 score of 2.1 (SD 1.2), who were started on dabigatran or rivaroxaban, were analysed for thromboembolic events and survival. Patients who had temporary or permanent discontinuation of NOAC were compared to patients on continuous NOAC treatment. RESULTS: Among 866 patients started on NOAC, 705 were treated without interruption, 84 patients had temporary interruption (69 because of planned invasive procedures, 10 due to bleeding, 5 for other causes) and 77 had permanent cessation of NOAC treatment. In patients without interruptions, the incidence of thromboembolic events was 1.0 (95% CI 0.4-2.1) per 100 patient-years, while in patients with interruption/cessation the rate of thromboembolic events was 21.6 (95% CI 10.3-45.2) per 100 patient-years, p < 0.001. There was a distinct clustering of thromboembolic events in the first weeks of NOAC discontinuation with the median occurring on day 14 (range 1-37 days) after discontinuation. CONCLUSION: Dabigatran and rivaroxaban offered good protection against thromboembolic events during treatment, but interruption of NOAC treatment increased the short-term thromboembolic risk more than 20-fold.


Subject(s)
Antithrombins/adverse effects , Atrial Fibrillation/drug therapy , Dabigatran/adverse effects , Factor Xa Inhibitors/adverse effects , Rivaroxaban/adverse effects , Thromboembolism/chemically induced , Thromboembolism/epidemiology , Aged , Atrial Fibrillation/complications , Female , Humans , Incidence , Male , Registries , Risk Factors , Slovenia/epidemiology
16.
Ann Clin Biochem ; 53(Pt 4): 446-51, 2016 Jul.
Article in English | MEDLINE | ID: mdl-26392631

ABSTRACT

BACKGROUND: Direct oral anticoagulant dabigatran was first introduced as a fixed-dose drug without routine coagulation monitoring, but current recommendations suggest that diluted thrombin time can be used to estimate plasma drug level. The aim of this study was to assess a diluted thrombin time assay based on the same thrombin reagent already used for traditional thrombin time measurements that reliably measure low to intermediate plasma dabigatran levels. METHODS: We included 44 patients with atrial fibrillation who started treatment with dabigatran 150 mg (23 patients) or 110 mg (21 patients) twice a day. Blood samples were collected at baseline (no dabigatran) and 2-4 weeks after the beginning of dabigatran therapy at trough and at peak. Plasma dabigatran levels were measured with diluted thrombin time and compared to liquid chromatography with tandem mass spectrometry as the reference method. The performance of the diluted thrombin time was compared to Hemoclot® Thrombin Inhibitor and Ecarin Chromogenic Assay. RESULTS: In ex vivo plasma samples, diluted thrombin time highly correlated with the liquid chromatography with tandem mass spectrometry (Pearson's R = 0.9799). In the low to intermediate range (dabigatran concentration ≤ 100 µg/L) diluted thrombin time correlated significantly more closely to the liquid chromatography with tandem mass spectrometry (R = 0.964) than Hemoclot® Thrombin Inhibitor (R = 0.935, p = 0.05) or Ecarin Chromogenic Assay (R = 0.915, p < 0.01). It was also the only functional assay without any significant bias in the low to intermediate range. Both trough and peak diluted thrombin time values were similar to liquid chromatography with tandem mass spectrometry. CONCLUSION: We conclude that the diluted thrombin time assay presented in this study reliably detects dabigatran and that it is superior to the Hemoclot® Thrombin Inhibitor assay in the low to intermediate range.


Subject(s)
Antithrombins/blood , Dabigatran/blood , Aged , Antithrombins/pharmacology , Dabigatran/pharmacology , Drug Monitoring , Humans , Limit of Detection , Reproducibility of Results , Thrombin Time
17.
Basic Clin Pharmacol Toxicol ; 117(5): 323-9, 2015 Nov.
Article in English | MEDLINE | ID: mdl-25981948

ABSTRACT

Routine laboratory monitoring is currently not recommended in patients receiving dabigatran despite its considerable variation in plasma concentration. However, in certain clinical situations, measurements of the dabigatran effect may be desirable. We aimed to assess the variability of dabigatran trough and peak concentration and explore the potential relationship between dabigatran concentration and adverse events. We included 44 patients with atrial fibrillation who started treatment with dabigatran 150 mg (D150) or 110 mg (D110) twice daily. They contributed 170 trough and peak blood samples that were collected 2-4 and 6-8 weeks after dabigatran initiation. Plasma dabigatran concentration was measured by LC-MS/MS and indirectly, by selected coagulation tests. D110 patients were older (74 ± 7 versus 68 ± 6 years), had lower creatinine clearance (68 ± 21 versus 92 ± 24 mL/min) and higher CHA2 DS2 -VASc score (3.1 ± 1.3 versus 2.3 ± 0.9) compared to D150 patients (all p < 0.05), but both had similar dabigatran concentrations in both trough and peak samples. Dabigatran concentrations varied less in trough than in peak samples (17.0 ± 13.6 versus 26.6 ± 19.2%, p = 0.02). During the 12-month follow-up, 4 patients on D150 and 6 on D110 suffered minor bleeding. There was no major bleeding or thromboembolic event. Patients with bleeding had significantly higher average trough dabigatran concentrations (93 ± 36 versus 72 ± 62 µg/L, p = 0.02) than patients without bleeding, while peak dabigatran values had no predictive value. Dabigatran dose selection according to the guidelines resulted in appropriate trough concentrations with acceptable repeatability. High trough concentrations may predispose patients to the risk of minor bleeding.


Subject(s)
Antithrombins/adverse effects , Antithrombins/blood , Atrial Fibrillation/drug therapy , Blood Coagulation/drug effects , Dabigatran/adverse effects , Dabigatran/blood , Drug Monitoring , Hemorrhage/chemically induced , Aged , Aged, 80 and over , Atrial Fibrillation/blood , Atrial Fibrillation/diagnosis , Blood Coagulation Tests , Chromatography, Liquid , Drug Monitoring/methods , Female , Humans , Male , Middle Aged , Predictive Value of Tests , Reproducibility of Results , Risk Assessment , Risk Factors , Tandem Mass Spectrometry , Time Factors , Treatment Outcome
18.
Wien Klin Wochenschr ; 127(11-12): 472-6, 2015 Jun.
Article in English | MEDLINE | ID: mdl-25829263

ABSTRACT

BACKGROUND: Patient education is essential for a safe and efficient oral anticoagulant treatment. We examined if a newly launched booklet with information on anticoagulant treatment with warfarin improved patient knowledge and the time spent in the therapeutic-range (TTR). METHODS: Standardized questionnaire was administered to 235 consecutive patients on warfarin to assess their baseline knowledge and readministered it 2 months after they received the booklet. A control group of 51 patients was interviewed only after the booklet had been distributed. RESULTS: Patient's knowledge at the baseline was unsatisfying (mean questionnaire score: 11/16) and a substantial progress was achieved after the educational intervention (mean questionnaire score: 13/16, p = 0.001). TTR is significantly increased after the intervention (63.4 ± 22.3 vs. 74.6 ± 23.8 %; p < 0.01). The mean questionnaire score and TTR after education were not different in the intervention and the control group. CONCLUSIONS: Knowledge about oral anticoagulant treatment and TTR is increased after the issue of the booklet in the majority of patients. However, for a small group of patients with unimproved knowledge new forms of education are needed.


Subject(s)
Health Literacy/statistics & numerical data , Medication Adherence/statistics & numerical data , Pamphlets , Patient Education as Topic/statistics & numerical data , Thromboembolism/prevention & control , Warfarin/administration & dosage , Administration, Oral , Aged , Anticoagulants/administration & dosage , Female , Health Knowledge, Attitudes, Practice , Humans , Male , Middle Aged , Slovenia/epidemiology , Thromboembolism/epidemiology , Treatment Outcome
19.
Thromb Res ; 133(6): 1011-5, 2014 Jun.
Article in English | MEDLINE | ID: mdl-24745719

ABSTRACT

INTRODUCTION: Pulmonary embolism (PE) is common in patients with deep venous thrombosis (DVT). The outcome of DVT with concomitant symptomatic PE is worse than the outcome of isolated DVT. The risk factors for DVT and simultaneous asymptomatic PE have not been systematically studied yet. AIM: To evaluate the frequency and risk factors for asymptomatic PE in patients with DVT. PATIENTS/METHODS: In 155 consecutive patients with a first episode of DVT and no PE symptoms, a ventilation-perfusion lung scan was performed. Body mass index (BMI) and waist-to-hip ratio (WHR) were calculated and concentrations of D-dimer, high-sensitivity CRP (hsCRP), tissue plasminogen activator (t-PA) and troponin were measured. Laboratory tests for thrombophilia were performed. RESULTS: Asymptomatic PE was present in 36% of patients. No differences in gender, age, BMI and WHR were found between the patients with and without PE. PE was more common in patients with proximal DVT than in those with distal DVT (42% vs. 17%, p<0.01), and in patients with unprovoked DVT compared to patients with provoked DVT (51% vs. 28%, p<0.01). The risk of silent PE was the highest in patients with unprovoked proximal DVT (OR, 6.9; 95% CI, 2.3-21.0). Patients with asymptomatic PE had significantly higher values of D-dimer, hsCRP, t-PA and troponin than patients with isolated DVT. CONCLUSIONS: Asymptomatic PE affected more than one third of patients with a first DVT. Unprovoked proximal DVT is the most important risk factor for the occurrence of silent PE.


Subject(s)
Pulmonary Embolism/etiology , Venous Thrombosis/complications , Female , Humans , Male , Middle Aged , Risk Factors , Treatment Outcome
20.
Heart Vessels ; 26(1): 31-8, 2011 Jan.
Article in English | MEDLINE | ID: mdl-20922535

ABSTRACT

Obesity is associated with impaired endothelial function, and this may lead to increased cardiovascular risk. To gain insight into the beneficial effects of diet-induced weight loss on endothelial function, endothelium-dependent, flow-mediated dilation (FMD) of the brachial artery and several metabolic and inflammatory markers were assessed in 40 obese women (BMI 34.9 ± 4.88 kg/m(2)) at baseline, after the 1st week and after 5 months on a low-calorie diet of 5.0 MJ/day. Twenty lean women served as controls. At entry, the obese women had a lower FMD than the lean women (7.7 ± 1.8 vs. 11.5 ± 4.2%, p < 0.001). After 1 week of the intervention and 4% reduction of BMI, FMD improved by 22% (p = 0.005), and a decrease in circulating triglycerides, insulin, leptin, tissue type plasminogen activator and its inhibitor, von Willebrand factor, C-reactive protein and tumor necrosis factor receptor 1 was observed. Improvement of FMD was associated only with a decrease in BMI (r = 0.39, p = 0.03). Twenty-two women completed the weight reduction program and reduced their BMI by 16%. FMD was further improved by 64% (to 12.4 ± 5.3%, p = 0.001) and became comparable to that of lean women. None of the significant changes in the observed parameters was associated with improvement of FMD at the end of the program. Improvements in obesity-related endothelial dysfunction began in the 1st week of dieting and continued during the following months of this simple non-pharmacological lifestyle modification to reach normalisation of endothelial function. The favourable effect of dieting on endothelial function is independent of the accompanying improvement of classical risk factors.


Subject(s)
Brachial Artery/physiopathology , Caloric Restriction , Endothelium, Vascular/physiopathology , Obesity/diet therapy , Vasodilation , Weight Loss , Adult , Biomarkers/blood , Brachial Artery/diagnostic imaging , Endothelium, Vascular/diagnostic imaging , Female , Fibrinolysis , Humans , Inflammation Mediators/blood , Linear Models , Middle Aged , Obesity/blood , Obesity/diagnostic imaging , Obesity/physiopathology , Recovery of Function , Slovenia , Time Factors , Treatment Outcome , Ultrasonography
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