Alenka Mavri

High D-dimer levels predict cardiovascular events in patients with chronic atrial fibrillation during oral anticoagulant therapy

Atrial fibrillation (AF) is associated with hemostatic abnormalities and increased risk of thrombotic cardiovascular events even during oral anticoagulant therapy (OAT). The aim of our study was to evaluate the predictive value of hemostatic markers for the risk of major cardiovascular events during OAT. The study group comprised 113 patients with chronic AF (70.2 +/- 5.4 years old, 60% men), referred for OAT. Established clinical risk factors and levels of prothrombin fragment 1+2 (F1+2), thrombin-antithrombin complexes (TAT), D-dimer, tissue plasminogen activator (t-PA) and plasminogen activator inhibitor 1 (PAI-1) antigen and activity, before and during OAT (after 3.9 +/- 0.7 months; INR 2.57 +/- 0.57) were determined. In all patients OAT significantly suppressed levels of F1+2 by 67%,TAT by 30% and D-dimer by 48% (all p <0.001). During an average follow-up of 44 months 22/111 (20%) patients suffered a combined cardiovascular event (stroke, myocardial infarction, peripheral vascular occlusion or vascular death). Patients with cardiovascular events were significantly older, had more frequent heart failure/systolic dysfunction and had significantly increased levels of D-dimer at entry (63 vs 39 ng/mL, p = 0.005) and during OAT (33 vs 18 ng/mL, p = 0.002), and of t-PA antigen at entry (14.3 vs 10.9 ng/mL, p = 0.02) and during OAT (15.0 vs 11.2 ng/mL, p = 0.05) (all values are medians). In multivariate Cox proportional hazard models, heart failure/systolic dysfunction (hazard ratio 2.91; 95% CI 1.17-7.26; p = 0.02), high levels of D-dimer on OAT (top vs. lower two quartiles) (hazard ratio 4.78, 95% CI 1.39-16.41; p = 0.01) and t-PA antigen levels (continuous variable) (hazard ratio 1.09; 95% CI 1.01-1.17; p = 0.02) were significantly associated with combined cardiovascular events. In conclusion, high levels of D-dimer and t-PA antigen during OAT are significant predictors of combined cardiovascular events in AF patients and, on this basis, could be useful additional markers of cardiovascular risk in such patients.

Diluted thrombin time reliably measures low to intermediate plasma dabigatran concentrations

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.

Dabigatran Concentration: Variability and Potential Bleeding Prediction In "Real-Life" Patients With Atrial Fibrillation.

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 CHA2DS2‐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.

Risk of Thromboembolic Events in Patients with Non-Valvular Atrial Fibrillation After Dabigatran or Rivaroxaban Discontinuation – Data from the Ljubljana Registry

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.

Unprovoked proximal venous thrombosis is associated with an increased risk of asymptomatic pulmonary embolism

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.

New educational approach for patients on warfarin improves knowledge and therapy control

SummaryBackgroundPatient 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).MethodsStandardized 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.ResultsPatient’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.ConclusionsKnowledge 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.

C0091 High levels of D-dimer and previous provoked venous thromboembolism are risk factors for recurrent idiopathic venous thrombosis

postoperative VTE; 2) determination of adequate, economicallyreasonable, comprehensive prophylaxis of VTE; 3) monitoring of effectiveness of treatment; 4) Early diagnosis and treatment of DVT and averting of complications. The aim of our study is to analyze the results of postoperative VTE prophylaxis and the possibilities for monitoring efficacy and safety. Methods: Results of VTE prophylaxis in 330 patients who had undergone various surgical procedures from 2005 to April 2012 at Botkin Hospital were analyzed. Age ranged from 25 to 84 years. Male patients numbered 75 (22.7%), female 255 (77.3%). General surgery patients numbered 178 (53.9%), gynecologic 108 (32.7%), urologic 44 (13.3%). Low molecular weight heparin (LMWH) was used for VTE prophylaxis (Enoxaparin Sodium Italfarmaco S.p.A. and Sanofi, Nadroparin Calcium – GlaxoSmithKline plc, Dalteparin Sodium – Pfizer, Inc.). In 124 patients (group A), LMWH was given 12 hrs prior to surgery until recovery of full activity (7–10 days), 90 (group B) received LMWH starting 6–12 hrs after surgery until full recovery, and 116 (controls) did not receive LMWH prophylaxis. For early detection of DVT, analysis of thrombus structure, 6determination of proximal thrombus edge, and monitoring of treatment efficacy, ultrasound scanning was performed before surgery and on the 7-8th day after surgery. Ventilation-perfusion (V/Q) lung scanning was performed in 15 patients. All 330 patients received some form of lower extremity compression to increase venous blood flow: VENOTEKS® THERAPY anti-embolism compression stockings in 280 (84.8%) patients and generic elastic bandages in 50 (15.2%) patients. Coagulation tests were performed in all patients. Results: In groupA, noDVTs or PEswere detected. In group B, DVTwas detected in 6 (6.7%)* and PE in 1 (1.1%)* patient. In the controls, DVT was detected in 32 (27.6%)* and PE in 4 (3.4%)* patients. *pb0.05 for DVT and PE rates between these groups. In 30 (79%) of the patientswith DVT, a decreasing trend in platelet count was observed following DVT diagnosis, indicating a continuing consumption of platelets. In groups A & B, a small increase in Soluble Fibrin Monomer Complex (SFMC) was observed, along with a decrease and subsequent increase in activity of Antithrombin III (AT III) and Protein C (PC). In patients with DVT, a decrease in SFMC was practically not seen; rather, discordance of AT III and PC was observed. Comment: In our experience, the optimal regime for combination VTE prophylaxis (LMWH in combinationwith lower extremity compression stockings/bandaging), with no increase in adverse events, is the regime in which LMWH prophylaxis is started prior to surgery.

Prevention of Venous Thromboembolism in Hip and Knee Arthroplasty

Patients with hip or knee arthroplasty are at a particularly high risk for venous thromboembolism. However, these events are highly preventable. For thromboprophylaxis we recommend combined mechanical (compression stockings, intermittent pneumatic compression or venous foot compression) and pharmacological (low molecular weight heparin, dabigatran etexilate or rivaroxaban) methods. In this article current guidelines for eff ective and safe thromboprophylaxis for hip and knee arthroplasty are presented.