Decrease of the atrial fibrillatory rate, increased organization of the atrial rhythm and termination of atrial fibrillation by AZD7009.

BACKGROUND: The atrial fibrillatory rate (AFR), on AZD7009 as compared to placebo, was investigated as a potential biomarker for electrophysiological effect in early antiarrhythmic drug development. METHODS: Patients with permanent AF received infusions of AZD7009 and placebo in an exploratory two-way, single-blind, randomized cross-over study. The ECG was continuously recorded, and following QRST cancellation the AFR, its standard deviation (SD), the exponential decay and the atrial electrogram amplitude were determined as 3-min averages. RESULTS: The mean AFR rapidly decreased by 43% from baseline (394 ± 38 to 225 ± 61 fibrillations/min, p=0.0003) on AZD7009, but not on placebo. The SD of the AFR and the exponential decay decreased in parallel. In 2 of 8 patients, termination of AF occurred after the AFR had decreased by 58% and 53%, respectively. CONCLUSIONS: The AFR may potentially serve as a biomarker of electrophysiological effects in early evaluation of rhythm control agents.

Comprehensive risk reduction in patients with atrial fibrillation: emerging diagnostic and therapeutic options--a report from the 3rd Atrial Fibrillation Competence NETwork/European Heart Rhythm Association consensus conference.

While management of atrial fibrillation (AF) patients is improved by guideline-conform application of anticoagulant therapy, rate control, rhythm control, and therapy of accompanying heart disease, the morbidity and mortality associated with AF remain unacceptably high. This paper describes the proceedings of the 3rd Atrial Fibrillation NETwork (AFNET)/European Heart Rhythm Association (EHRA) consensus conference that convened over 60 scientists and representatives from industry to jointly discuss emerging therapeutic and diagnostic improvements to achieve better management of AF patients. The paper covers four chapters: (i) risk factors and risk markers for AF; (ii) pathophysiological classification of AF; (iii) relevance of monitored AF duration for AF-related outcomes; and (iv) perspectives and needs for implementing better antithrombotic therapy. Relevant published literature for each section is covered, and suggestions for the improvement of management in each area are put forward. Combined, the propositions formulate a perspective to implement comprehensive management in AF.

QT response after a test dose and during maintenance therapy with AZD1305 in patients with atrial fibrillation: a double-blind, randomized, placebo-controlled trial.

BACKGROUND AND OBJECTIVE: AZD1305 is an investigational antiarrhythmic agent that prolongs refractoriness through combined potassium and sodium channel inhibition. This study aimed to explore the utility of a test dose in predicting QT interval corrected according to Fridericia's formula (QTcF) during subsequent maintenance treatment with AZD1305. METHODS: This was a randomized, double-blind, parallel-group, placebo-controlled trial carried out at multiple hospital cardiac facilities in Denmark, Norway, Poland, Slovakia, and Sweden. Patients with documented atrial fibrillation (AF) but currently in stable sinus rhythm for ≥2 hours and ≤90 days were eligible for inclusion. Patients were randomized in a 1 : 1 : 1 ratio to receive AZD1305 extended-release or matching placebo tablets as follows: group A - test dose 250 mg, evening dose 125 mg on day 1, maintenance dose 125 mg twice daily; group B - test dose 500 mg, placebo evening dose, maintenance dose 125 mg twice daily; placebo group - placebo test and maintenance dose. Maintenance dosing was for 9 days. QTcF >550 ms at any time during the in-patient phase or >500 ms after discharge (day 4) were predefined study drug discontinuation criteria. The main outcome measure was the relationship between QTcF following the test dose and during maintenance treatment. RESULTS: Sixty-five patients were randomized (n = 21, 22, and 22 in group A, group B, and the placebo group, respectively). AZD1305 dose-dependently increased QTcF. There was a positive, linear correlation between the change in QTcF during the first 6 hours after the test dose and during the maintenance phase. Three patients, all from group B, discontinued treatment on day 1 due to QTcF >550 ms. All other patients completed the study without events related to QT prolongation. There was a trend for reduced AF recurrence with AZD1305 compared with placebo. CONCLUSION: In this exploratory study a test dose predicted the QT response during maintenance treatment with AZD1305 and may thus be employed in further studies. [ClinicalTrials.gov Identifier: NCT00643448].

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.

Prediction of drug-related morphological changes of the T wave.

OBJECTIVES: To describe the characteristics of patients presenting with morphological T wave changes that lead to measurement difficulties, and to identify possible predictors of such changes at baseline and early after start of treatment. DESIGN: ECGs from 145 patients receiving a combined potassium and sodium channel blocking agent for conversion of atrial fibrillation (AF), underwent semiautomatic analysis in a digitalized high-precision analysis program. In 15 patients, one or more ECGs were identified as difficult to interpret due to morphological T wave changes. They were compared with the 130 patients without such changes. RESULTS: A history of cardiac failure (p=0.027), a smaller left atrial area (p=0.010) and a longer QT(tang) minus QT(top) interval (p<0.001) at baseline was significantly more frequent as compared to the controls. Identified patients also had somewhat longer baseline QT interval duration (median QT(cB) 432 vs. 408 ms, N.S.) and a larger proportion of them were females (47% vs. 27%, N.S.). After start of infusion the QT(cB) became significantly longer in identified patients than in controls (p=0.012). CONCLUSIONS: Independent predictors of subsequent morphological changes were found at baseline and shortly after start of treatment, and may be of use to identify individuals with a reduced repolarization reserve.

T wave inversions following ablation of 125 posteroseptal accessory pathways.

BACKGROUND: Cardiac memory, electrophysiological remodeling induced by periods of altered ventricular activation, has been observed after resumption of normal activation following ablation of overt accessory pathways. We studied the occurrence and temporal characteristics of cardiac memory (inferior T wave inversions) after ablation of overt posteroseptal accessory pathways. METHODS: T wave changes were assessed in the frontal plane (leads II, aVF, and III) up to one year after the ablation in 125 consecutive patients. T wave polarity immediately after ablation was compared with the pre ablation delta wave polarity and the dominant QRS force in each lead. The number of inferior leads (0-3) with post ablation T wave changes (estimate of degree of cardiac memory) was analyzed in relation to estimates of the degree of preexcitation (accessory pathway refractoriness and QRS duration) prior to ablation. RESULTS: Electrocardiogram (ECG) signs of cardiac memory were present in 123 (98%) of the patients within one day after ablation. The post ablation T wave vector had the same direction as the vector of the pre-excited QRS complex (and delta wave) creating inferior T wave inversions. There was no correlation between the degree of preexcitation pre ablation and the extent of cardiac memory post ablation. A majority (about 90%) of ECGs recorded 3-6 months after the procedure, showed complete or almost complete normalization. CONCLUSIONS: T wave inversions were present in the vast majority of patients, persisted in some patients beyond 3 months, and might be misinterpreted as inferior wall ischemia.