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- Title
QT Response after a Test Dose and during Maintenance Therapy with AZD1305 in Patients with Atrial Fibrillation.
- Authors
Egstrup, Kenneth; Bergfeldt, Lennart; Duris, Tibor; Gullestad, Lars; Kochmanski, Marek; Kuśnierz, Barbara; Nielsen, Tonny; Sawicki, Stefan; Aunes-Jansson, Maria; Edvardsson, Nils; Frison, Lars; Johansson, Susanne; Berggren, Anders
- Abstract
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 inDenmark,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 receiveAZD1305 extended-release or matching placebo tablets as follows: group A - test dose 250mg, evening dose 125mg on day 1, maintenance dose 125mg twice daily; group B - test dose 500 mg, placebo evening dose, maintenance dose 125mg twice daily; placebo group - placebo test andmaintenance dose.Maintenance dosing was for 9 days. QTcF >550ms at any time during the in-patient phase or >500ms 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.
- Subjects
EUROPE; AMBULATORY electrocardiography; ATRIAL fibrillation; CONFIDENCE intervals; CONTROLLED release preparations; STATISTICAL correlation; DOSE-effect relationship in pharmacology; MEDICAL cooperation; MYOCARDIAL depressants; PROBABILITY theory; RESEARCH; RESEARCH funding; STATISTICS; SURVIVAL analysis (Biometry); T-test (Statistics); DISEASE relapse; DATA analysis; RANDOMIZED controlled trials; PROPORTIONAL hazards models; BLIND experiment; ACYCLIC acids; DESCRIPTIVE statistics
- Publication
American Journal of Cardiovascular Drugs, 2011, Vol 11, Issue 3, p199
- ISSN
1175-3277
- Publication type
Article
- DOI
10.2165/11591750-000000000-00000