Exposure-response for biomarkers of anticoagulant effects by the oral direct thrombin inhibitor AZD0837 in patients with atrial fibrillation.

AIMS: AZD0837 is a novel oral anticoagulant investigated in clinical studies for stroke prevention in patients with atrial fibrillation (AF). It is bioconverted to its active form, AR-H067637, a potent, specific and reversible thrombin inhibitor. The effects on coagulation biomarkers were correlated with the pharmacokinetic (PK) exposure of AR-H067637 to guide selection of the effective dose regimen for a confirmatory efficacy study in AF patients. METHODS: Blood samples were obtained from 601 AF patients randomized to one of four doses of AZD0837 (blinded treatment) or dose-adjusted vitamin K antagonists (VKA, open treatment) for 3-9 months. A pharmacodynamic model was developed to describe the time course of the AR-H067637 exposure dependent effects and the effect of VKA on fibrin D-dimer. The thrombin generation measured ex vivo in venous plasma was also investigated. RESULTS: The PK exposure of AR-H067637 was stable with an interindividual variability of 33% and no or minor influence of patient demographics or comedications. For AZD0837, D-dimer levels decreased with more rapid onset than for VKA. The decrease in D-dimer levels correlated with steady-state plasma concentrations (C(ss)) of AR-H067637, with a maximum decrease of baseline D-dimer levels estimated to approximately 60% for both AZD0837 and VKA therapy. The effect on thrombin generation correlated closely with the plasma concentration of AR-H067637. CONCLUSIONS: The effects on thrombin generation and fibrin D-dimer levels correlated with the plasma concentration of its active form and provided comparable effects to well-controlled VKA therapy at an exposure at least corresponding to the 300 mg once daily dose of AZD0837.

Predictors of new onset atrial fibrillation during 10-year follow-up after first-ever ischemic stroke.

BACKGROUND: Paroxysmal atrial fibrillation (AF) may be underdiagnosed in ischemic stroke patients but may be pivotal for initiation of oral anticoagulation therapy. We assessed clinical and ECG predictors of new-onset AF during 10-year follow-up (FU) in ischemic stroke patients. METHODS: The study sample comprised of 227 first-ever ischemic stroke patients without AF (median age 73, interquartile range 25%-75% 63-80years, 92 female) and 1:1 age- and gender-matched controls without stroke and AF enrolled in the Lund Stroke Register from March 2001 to February 2002. New-onset AF during FU was assessed by screening through regional ECG database and by record linkage with Swedish National Patient Register. The standard 12-lead sinus rhythm ECGs at stroke admission were retrieved from electronic database and digitally processed. Clinical baseline characteristics were studied using medical records. RESULTS: During FU, AF was found in 39 stroke patients and 30 controls, p=0.296. In stroke patients in multivariate Cox regression analysis AF was associated with hypertension (HR 3.45 CI 95% 1.40-3.49, p=0.007) and QRS duration (HR 1.02 CI 95% 1.00-1.03, p=0.049). High cardiovascular risk was predictive for AF development: for CHADS2≥4 HR 2.46 CI 95% 1.45-4.18, p=0.001 and for CHA2DS2-VASc≥5 HR 2.29 CI 95% 1.43-3.68, p=0.001. New onset AF was not associated with baseline ischemic stroke: HR 1.46 95% CI 0.90-2.35, p=0.121. CONCLUSION: High CHADS2 and CHA2DS2-VASc scores, but not baseline ischemic stroke, predict new onset AF in FU. QRS duration might be considered a potential risk marker for prediction of AF after ischemic stroke.

Oral direct thrombin inhibitor AZD0837 for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation: a Phase II study of AZD0837 in patients who are appropriate for but unable or unwilling to take vitamin K antagonist therapy.

BACKGROUND: Some patients with atrial fibrillation (AF) cannot be treated with vitamin K antagonists (VKAs) and will therefore not receive effective thromboprophylaxis. The primary objective of the present Phase II trial (NCT00623779) was to assess the feasibility of conducting a study with a novel oral anticoagulant, the direct thrombin inhibitor AZD0837, in patients with AF unable or unwilling to take warfarin, by evaluation of dropout rates and compliance. METHODS: Patients were randomised to receive AZD0837 extended-release tablets 150 mg (n=43) or 300 mg (n = 42) once daily, or standard therapy (no treatment, aspirin 75-325 mg or clopidogrel 75 mg once daily; n = 46) for a median treatment duration of 6 weeks. RESULTS: Reasons for patients not being treated with warfarin were: refusal or permanent cessation decided by the patient (64.8%), inability to keep international normalised ratio 2-3 over a 3-month period (23.2%), physician assessment that VKA was inappropriate (20.4%) and warfarin allergy (2.8%). Compliance with treatment (mean ± SD) was 97.0 ± 16.5% for AZD0837 150 mg and 99.8 ± 1.4% for 300 mg. Compliance with study visits was high (mean 93-98%). The numbers of dropouts were four, six and three, whilst minor or clinically significant minor bleeds were reported in zero, five and two patients in the AZD0837 150 mg, 300 mg and standard-therapy groups, respectively. No major bleeds were reported. Both doses of AZD0837 reduced levels of fibrin D-dimer and prolonged activated partial thromboplastin time, ecarin clotting time and thrombin clotting time. CONCLUSIONS: AZD0837 had a good safety profile during this study, including a low incidence of bleeding events, with effective anticoagulation on pharmacodynamic parameters. A larger study in AF patients unable or unwilling to take warfarin is feasible, as judged by compliance and dropout rates.

Safety and tolerability of an immediate-release formulation of theoral direct thrombin inhibitor AZD0837 in the prevention of stroke and systemic embolism in patients with atrial fibrillation.

AZD0837 is an investigational oral anticoagulant which is converted to the active form, AR-H067637, a selective direct thrombin inhibitor. The present study, a multicentre, randomised, parallel-group, dose-guiding study, assessed the safety and tolerability of an immediate-release formulation of AZD0837 compared with dose-adjusted warfarin in the prevention of stroke and systemic embolic events in atrial fibrillation (AF) patients. Two hundred fifty AF patients with at least one additional risk factor for stroke were randomised to receive either immediate-release AZD0837 (150mg twice daily [bid] or 350mg bid, blinded treatment) or dose-adjusted warfarin (international normalised ratio 2.0-3.0, open treatment) for three months. The safety and tolerability of 150mg bid AZD0837 appeared to be as good as that of warfarin. Total bleeding events were six with 150mg bid AZD0837, 15 with 350mg bid AZD0837 and eight with warfarin. Alanine aminotransferase elevations (>3xupper limit of normal) were infrequent, without apparent differences between treatment groups. A numerically higher incidence of serious adverse events was observed with 350mg bid AZD0837 compared with 150mg bid, with six of 13 being cardiac related, all with different diagnoses. An increase in mean serum creatinine of approximately 10% was observed in both AZD0837 groups, which returned to baseline after completion of therapy. There were no strokes, transient ischaemic attacks or cerebral haemorrhages with any of the treatments. In conclusion, the safety and tolerability of 150mg bid immediate-release AZD0837 appeared to be as good as that of dose-adjusted warfarin. However, larger studies will be needed to define the safety profile of AZD0837.

Oral direct thrombin inhibitor AZD0837 for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation: a randomized dose-guiding, safety, and tolerability study of four doses of AZD0837 vs. vitamin K antagonists.

AIMS: Oral anticoagulation with vitamin K antagonists (VKAs) for stroke prevention in atrial fibrillation (AF) is effective but has significant limitations. AZD0837, a new oral anticoagulant, is a prodrug converted to a selective and reversible direct thrombin inhibitor (AR-H067637). We report from a Phase II randomized, dose-guiding study (NCT00684307) to assess safety, tolerability, pharmacokinetics, and pharmacodynamics of extended-release AZD0837 in patients with AF. METHODS AND RESULTS: Atrial fibrillation patients (n = 955) with > or =1 additional risk factor for stroke were randomized to receive AZD0837 (150, 300, or 450 mg once daily or 200 mg twice daily) or VKA (international normalized ratio 2-3, target 2.5) for 3-9 months. Approximately 30% of patients were naïve to VKA treatment. Total bleeding events were similar or lower in all AZD0837 groups (5.3-14.7%, mean exposure 138-145 days) vs. VKA (14.5%, mean exposure 161 days), with fewer clinically relevant bleeding events on AZD0837 150 and 300 mg once daily. Adverse events were similar between treatment groups; with AZD0837, the most common were gastrointestinal disorders (e.g. diarrhoea, flatulence, or nausea). d-Dimer, used as a biomarker of thrombogenesis, decreased in all groups in VKA-naïve subjects with treatment, whereas in VKA pre-treated patients, d-dimer levels started low and remained low in all groups. As expected, only a few strokes or systemic embolic events occurred. In the AZD0837 groups, mean S-creatinine increased by approximately 10% from baseline and returned to baseline following treatment cessation. The frequency of serum alanine aminotransferase > or =3x upper limit of normal was similar for AZD0837 and VKA. CONCLUSION: AZD0837 was generally well tolerated at all doses tested. AZD0837 treatment at an exposure corresponding to the 300 mg od dose in this study provides similar suppression of thrombogenesis at a potentially lower bleeding risk compared with dose-adjusted VKA. This study is registered with ClinicalTrials.gov, number NCT00684307.

Atrial fibrillatory rate and risk of stroke in atrial fibrillation.

AIMS: In atrial fibrillation (AF), a relation between electrocardiogram (ECG) parameters such as fibrillatory wave amplitude and stroke has been sought with conflicting results. In this study, we tested the hypothesis that the atrial fibrillatory rate of surface ECG lead V1 is related to stroke risk and may consequently be helpful for identifying high-risk patients. METHODS AND RESULTS: Atrial fibrillatory rate of 79 consecutive patients with AF and embolic stroke (age 83 +/- 7 years, 41% male) was compared with those of a matched AF population without stroke (n = 79). Atrial fibrillatory rate was determined from the surface ECG using spatiotemporal QRST cancellation and time-frequency analysis of lead V1. There was no significant difference in any clinical or echocardiographic variable in patients with stroke compared with AF controls without stroke. Atrial fibrillatory rate measured 373 +/- 55 fibrillations per minute (fpm; range 235-505 fpm) in the entire population. There was no fibrillatory rate difference between stroke patients (369 +/- 54 fpm, range 256-505 fpm) and AF controls without stroke (378 +/- 56 fpm, range 235-488 fpm). There was an inverse correlation between fibrillatory rate and age (R = -0.219, P = 0.006). Individuals aged >or=85 years had a significantly lower fibrillatory rate (356 +/- 44 fpm) than individuals aged 65-74 years (384 +/- 56 fpm, P = 0.033) and individuals aged 75-84 years (384 +/- 60 fpm, P = 0.016). In those subgroups, fibrillatory rates were, however, also similar in stroke patients and AF controls. CONCLUSION: Atrial fibrillatory rate obtained from surface ECG lead V1 is not a risk marker for stroke in AF.

Analysis of atrial fibrillation: from electrocardiogram signal processing to clinical management.

The analysis of atrial fibrillation in non-invasive ECG recordings has received considerable attention in recent years, spurring the development of signal processing techniques for more advanced characterization of the atrial waveforms than previously available. The present paper gives an overview of different approaches to the extraction of atrial activity in the ECG and to the characterization of the resulting atrial signal with respect to its spectral properties. So far, the repetition rate of the atrial waves is the most studied parameter and its significance in clinical management is briefly considered, including the identification of pathomechanisms and prediction of therapy efficacy.

Permanent atrial fibrillation in patients without structural heart disease is not associated with signs of infection by Chlamydia pneumoniae and Helicobacter pylori.

OBJECTIVE: The objective of this study was to explore the role of Chlamydia pneumoniae and Helicobacter pylori infections in patients with idiopathic permanent atrial fibrillation. METHODS AND RESULTS: Sera from 72 patients with permanent atrial fibrillation without structural heart disease (mean age 69.6 years, 23 women) were analysed for IgG antibodies against Chlamydia pneumoniae and Helicobacter pylori and compared in a I:I age- and sex-matched case:control manner with those pooled from a healthy reference population of 72 individuals from the same geographical area. After excluding patients with other possible or definite factors known either to cause atrial fibrillation or to affect the prevalence of seropositivity to these agents, the frequency of seropositivity due to one or both of the infectious agents was compared. Serum C-reactive protein (CRP) level was assessed using immunoturbidimetry technique. Both agents were equally common in men and women. Neither seropositivity to Chlamydia pneumoniae (76% vs. 83%, patients vs. control subjects, ns) nor to Helicobacter pylori (57% contra 55%, patients vs. controls, ns) alone reached significance in the comparisons between patients with atrial fibrillation and control subjects. Serum CRP was higher in patients with AF (5.3 mg/L vs. 2.8 mg/L, P < 0.001). CONCLUSIONS: Though presence of permanent AF is associated with elevated CRP levels, this elevation is not the result of earlier infections with Chlamydia pneumoniae or Helicobacter pylori or their combination.