A phase 1 trial of AP30663, a KCa2 channel inhibitor in development for conversion of atrial fibrillation.

AIMS: AP30663 is a novel compound under development for pharmacological conversion of atrial fibrillation by targeting the small conductance Ca2+ activated K+ (KCa2) channel. The aim of this extension phase 1 study was to test AP30663 at higher single doses compared to the first-in-human trial. METHODS: Sixteen healthy male volunteers were randomized into 2 cohorts: 6- and 8-mg/kg intravenous single-dose administration of AP30663 vs. placebo. Safety, pharmacokinetic and pharmacodynamic data were collected. RESULTS: AP30663 was associated with mild and transient infusion site reactions with no clustering of other adverse events but with an estimated maximum mean QTcF interval prolongation of 45.2 ms (95% confidence interval 31.5-58.9) in the 6 mg/kg dose level and 50.4 ms (95% confidence interval 36.7-64.0) with 8 mg/kg. Pharmacokinetics was dose proportional with terminal half-life of around 3 h. CONCLUSION: AP30663 in doses up to 8 mg/kg was associated with mild and transient infusion site reactions and an increase of the QTcF interval. Supporting Information support that the QTc effect may be explained by an off-target inhibition of the IKr channel.

Inhibition of the KCa2 potassium channel in atrial fibrillation: a randomized phase 2 trial.

Existing antiarrhythmic drugs to treat atrial fibrillation (AF) have incomplete efficacy, contraindications and adverse effects, including proarrhythmia. AP30663, an inhibitor of the KCa2 channel, has demonstrated AF efficacy in animals; however, its efficacy in humans with AF is unknown. Here we conducted a phase 2 trial in which patients with a current episode of AF lasting for 7 days or less were randomized to receive an intravenous infusion of 3 or 5 mg kg-1 AP30663 or placebo. The trial was prematurely discontinued because of slow enrollment during the coronavirus disease 2019 pandemic. The primary endpoint of the trial was cardioversion from AF to sinus rhythm within 90 min from the start of the infusion, analyzed with Bayesian statistics. Among 59 patients randomized and included in the efficacy analyses, the primary endpoint occurred in 42% (5 of 12), 55% (12 of 22) and 0% (0 of 25) of patients treated with 3 mg kg-1 AP30663, 5 mg kg-1 AP30663 or placebo, respectively. Both doses demonstrated more than 99.9% probability of superiority over placebo, surpassing the prespecified 95% threshold. The mean time to cardioversion, a secondary endpoint, was 47 (s.d. = 23) and 41 (s.d. = 24) minutes for 3 mg kg-1 and 5 mg kg-1 AP30663, respectively. AP30663 caused a transient increase in the QTcF interval, with a maximum mean effect of 37.7 ms for the 5 mg kg-1 dose. For both dose groups, no ventricular arrhythmias occurred and adverse event rates were comparable to the placebo group. AP30663 demonstrated AF cardioversion efficacy in patients with recent-onset AF episodes. KCa2 channel inhibition may be an attractive mechanism for rhythm control of AF that should be studied further in randomized trials. ClinicalTrials.gov registration: NCT04571385 .

All-cause mortality trends in patients hospitalized for atrial fibrillation in Sweden: Role of age, stroke risk, and education.

Background: The incidence of atrial fibrillation (AF) has long been increasing, and AF is associated with increased mortality. Over time, mortality trends may differ between subgroups depending on their underlying risk patterns and treatments. Aim: To explore all-cause-mortality trends over time in patients hospitalized for incident AF, and the effects of age, stroke risk, and education level. Methods and results: Patients hospitalized for incident AF between January 1995 and December 2003 were selected from Swedish national registries. Based on date of index admission, patients were divided into four cohorts and followed for five years. Age- and sex-matched controls were selected. Kaplan-Meier estimates and Cox regressions with trend analysis were used for statistical evaluation. There were 64,489 patients (mean age 72 ± 10.1 years) and 116,893 controls. There was a significantly decreasing trend in the relative risk of all-cause mortality in AF patients over time, with a trend hazard ratio of 0.94 (95 % confidence interval [CI] 0.92-0.96, p < 0.001) in women and 0.91 (95 % CI 0.89-0.93, p < 0.001) in men. The mortality trends did not differ significantly between AF patients and controls. The mortality risk remained unchanged in women aged 18-64 years, in patients with low stroke risk, and in patients with post-secondary education. Conclusion: The all-cause mortality risk decreased over time in both patients and controls, but subgroup analysis revealed an unchanged mortality trend in women aged 18-64 years, in patients with low stroke risk, and in patients with post-secondary education.

The contribution of intermittent handheld electrocardiogram and continuous electrocardiogram monitoring with an implantable loop recorder to detect incident and recurrent atrial fibrillation during 1 year after coronary artery bypass graft surgery: A prospective cohort study.

BACKGROUND: Atrial fibrillation (AF) is common after coronary artery bypass graft (CABG) surgery. OBJECTIVE: To evaluate the incidence and recurrence rate of AF during 1 year after CABG surgery. We also aimed at calculating the AF burden and compare long-term intermittent vs continuous electrocardiogram (ECG) monitoring. METHODS: Forty patients scheduled for CABG surgery were equipped with an implantable loop recorder (ILR). After discharge, they carried out handheld ECG 3 times daily during the first 30 postoperative days and during 2 weeks at 3 and 12 months. During hospital stay they were monitored with telemetry. RESULTS: Altogether 27 of 40 (68%) patients were diagnosed with AF, 24 during the first month (21 in-hospital and 3 after discharge) and 3 during months 2-12. Three patients progressed into persistent AF. In addition, 17 patients had AF recurrence, 9 of them after the first 30 days. In patients with paroxysmal AF, the AF burden was low, 0.1% (interquartile range [IQR] 0.02%-0.3%). Patients with AF had higher CHA2DS2-VASc scores than non-AF patients: median 4 (IQR 3-4) and 3 (IQR 2-3.5), respectively, P = .006. The handheld ECG identified 45% (9/20) of the patients with AF episodes identified with continuous ECG monitoring with the ILR after discharge from hospital, P = .001. CONCLUSIONS: Patients with AF during the postoperative hospitalization showed a high likelihood of recurrent AF, usually within 30 days. Continuous ECG monitoring with an ILR was superior to the handheld ECG for detecting patients with AF. The AF burden was low.

First Clinical Study with AP30663 - a KCa 2 Channel Inhibitor in Development for Conversion of Atrial Fibrillation.

Pharmacological cardioversion of atrial fibrillation (AF) is frequently inefficacious. AP30663, a small conductance Ca2+ activated K+ (KCa 2) channel blocker, prolonged the atrial effective refractory period in preclinical studies and subsequently converted AF into normal sinus rhythm. This first-in-human study evaluated the safety and tolerability, and pharmacokinetic (PK) and pharmacodynamic (PD) effects were explored. Forty-seven healthy male volunteers (23.7 ± 3.0 years) received AP30663 intravenously in ascending doses. Due to infusion site reactions, changes to the formulation and administration were implemented in the latter 24 volunteers. Extractions from a 24-hour continuous electrocardiogram were used to evaluate the PD effect of AP30663. Data were analyzed with a repeated measure analysis of covariance, noncompartmental analysis, and concentration-effect analysis. In total, 33 of 34 adverse events considered related to AP30663 exposure were related to the infusion site, mild in severity, and temporary in nature, although full recovery took up to 110 days. After formulation and administration changes, the local infusion site reaction remained, but the median duration was shorter despite higher dose levels. AP30663 displayed a less than dose proportional increase in peak plasma concentration (Cmax ) and a terminal half-life of around 5 hours. In healthy volunteers, no effect of AP30663 was observed on electrocardiographic parameters, other than a concentration-dependent effect on the corrected QT Fridericia's formula interval (+18.8 ± 4.3 ms for the highest dose level compared with time matched placebo). In conclusion, administration of AP30663, a novel KCa 2 channel inhibitor, was safe and well-tolerated systemically in humans, supporting further development in patients with AF undergoing cardioversion.

Inhibition of KCa2 Channels Decreased the Risk of Ventricular Arrhythmia in the Guinea Pig Heart During Induced Hypokalemia.

BACKGROUND: Hypokalemia reduces the cardiac repolarization reserve. This prolongs the QT-interval and increases the risk of ventricular arrhythmia; a risk that is exacerbated by administration of classical class 3 anti-arrhythmic agents.Small conductance Ca2+-activated K+-channels (KCa2) are a promising new atrial selective target for treatment of atrial fibrillation. Under physiological conditions KCa2 plays a minor role in ventricular repolarization. However, this might change under hypokalemia because of concomitant increases in ventriculay -60r intracellur Ca2+. PURPOSE: To study the effects of pharmacological KCa2 channel inhibition by the compounds AP14145, ICA, or AP30663 under hypokalemic conditions as compared to dofetilide and hypokalemia alone time-matched controls (TMC). METHODS: The current at +10 mV was compared in HEK293 cells stably expressing KCa2.3 perfused first with normo- and then hypokalemic solutions (4 mM K+ and 2.5 mM K+, respectively). Guinea pig hearts were isolated and perfused with normokalemic (4 mM K+) Krebs-Henseleit solution, followed by perfusion with drug or vehicle control. The perfusion was then changed to hypokalemic solution (2.5 mM K+) in presence of drug. 30 animals were randomly assigned to 5 groups: ICA, AP14145, AP30663, dofetilide, or TMC. QT-interval, the interval from the peak to the end of the T wave (Tp-Te), ventricular effective refractory period (VERP), arrhythmia score, and ventricular fibrillation (VF) incidence were recorded. RESULTS: Hypokalemia slightly increased KCa2.3 current compared to normokalemia. Application of KCa2 channel inhibitors and dofetilide prolonged the QT interval corrected for heart rate. Dofetilide, but none of the KCa2 channel inhibitors increased Tp-Te during hypokalemia. During hypokalemia 4/6 hearts in the TMC group developed VF (two spontaneously, two by S1S2 stimulation) whereas 5/6 hearts developed VF in the dofetilide group (two spontaneously, three by S1S2 stimulation). In comparison, 0/6, 1/6, and 1/6 hearts developed VF when treated with the KCa2 channel inhibitors AP30663, ICA, or AP14145, respectively. CONCLUSION: Hypokalemia was associated with an increased incidence of VF, an effect that also seen in the presence of dofetilide. In comparison, the structurally and functionally different KCa2 channel inhibitors, ICA, AP14145, and AP30663 protected the heart from hypokalemia induced VF. These results support that KCa2 inhibition may be associated with a better safety and tolerability profile than dofetilide.

Mechanisms of Action of the KCa2-Negative Modulator AP30663, a Novel Compound in Development for Treatment of Atrial Fibrillation in Man.

AIMS: Small conductance Ca2+-activated K+ channels (SK channels, KCa2) are a new target for treatment of atrial fibrillation (AF). AP30663 is a small molecule inhibitor of KCa2 channels that is currently in clinical development for treatment of AF. The aim of this study is to present the electrophysiological profile and mechanism of action of AP30663 and its efficacy in prolonging atrial refractoriness in rodents, and by bioinformatic analysis investigate if genetic variants in KCNN2 or KCNN3 influence the expression level of these in human heart tissue. METHODS AND RESULTS: Whole-cell and inside-out patch-clamp recordings of heterologously expressed KCa2 channels revealed that AP30663 inhibits KCa2 channels with minor effects on other relevant cardiac ion channels. AP30663 modulates the KCa2.3 channel by right-shifting the Ca2+-activation curve. In isolated guinea pig hearts AP30663 significantly prolonged the atrial effective refractory period (AERP) with minor effects on the QT-interval corrected for heart rate. Similarly, in anaesthetized rats 5 and 10 mg/kg of AP30663 changed the AERP to 130.7±5.4% and 189.9±18.6 of baseline values. The expression quantitative trait loci analyses revealed that the genome wide association studies for AF SNP rs13376333 in KCNN3 is associated with increased mRNA expression of KCNN3 in human atrial appendage tissue. CONCLUSIONS: AP30663 is a novel negative allosteric modulator of KCa2 channels that concentration-dependently prolonged rodent atrial refractoriness with minor effects on the QT-interval. Moreover, AF associated SNPs in KCNN3 influence KCNN3 mRNA expression in human atrial tissue. These properties support continued development of AP30663 for treatment of AF in man.

Inhibition of KCa2 and Kv11.1 Channels in Pigs With Left Ventricular Dysfunction.

BACKGROUND: Inhibition of KCa2 channels, conducting IKCa, can convert atrial fibrillation (AF) to sinus rhythm and protect against its induction. IKCa inhibition has been shown to possess functional atrial selectivity with minor effects on ventricles. Under pathophysiological conditions with ventricular remodeling, however, inhibiting IKCa can exhibit both proarrhythmic and antiarrhythmic ventricular effects. The aim of this study was to evaluate the effects of the IKCa inhibitor AP14145, when given before or after the IKr blocker dofetilide, on cardiac function and ventricular proarrhythmia markers in pigs with or without left ventricular dysfunction (LVD). METHODS: Landrace pigs were randomized into an AF group (n = 6) and two control groups: SHAM1 (n = 8) and SHAM2 (n = 4). AF pigs were atrially tachypaced (A-TP) for 43 ± 4 days until sustained AF and LVD developed. A-TP and SHAM1 pigs received 20 mg/kg AP14145 followed by 100 µg/kg dofetilide whereas SHAM2 pigs received the same drugs in the opposite order. Proarrhythmic markers such as short-term variability of QT (STVQT) and RR (STVRR) intervals, and the number of premature ventricular complexes (PVCs) were measured at baseline and after administration of drugs. The influence on cardiac function was assessed by measuring cardiac output, stroke volume, and relevant echocardiographic parameters. RESULTS: IKCa inhibition by AP14145 did not increase STVQT or STVRR in any of the pigs. IKr inhibition by dofetilide markedly increased STVQT in the A-TP pigs, but not in SHAM operated pigs. Upon infusion of AP14145 the number of PVCs decreased or remained unchanged both when AP14145 was infused after baseline and after dofetilide. Conversely, the number of PVCs increased or remained unchanged upon dofetilide infusion. Neither AP14145 nor dofetilide affected relevant echocardiographic parameters, cardiac output, or stroke volume in any of the groups. CONCLUSION: IKCa inhibition with AP14145 was not proarrhythmic in healthy pigs, or in the presence of LVD resulting from A-TP. In pigs already challenged with 100 µg/kg dofetilide there were no signs of proarrhythmia when 20 mg/kg AP14145 were infused. KCa2 channel inhibition did not affect cardiac function, implying that KCa2 inhibitors can be administered safely also in the presence of LV dysfunction.

Characterization of Atrial and Ventricular Structural Remodeling in a Porcine Model of Atrial Fibrillation Induced by Atrial Tachypacing.

Background: Atrial fibrillation (AF) is characterized by electrical and structural remodeling. Irregular and/or fast atrio-ventricular (AV) conduction during AF can result in AV dyssynchrony, tachymyopathy, pressure and volume overload with subsequent dilatation, valve regurgitation, and ventricular dysfunction with progression to heart failure. Objective: To gain further insight into the myocardial pathophysiological changes induced by right atrial tachypacing (A-TP) in a large animal model. Methods: A total of 28 Landrace pigs were randomized as 14 into AF-induced A-TP group and 14 pigs to control group. AF pigs were tachypaced for 43 ± 4 days until in sustained AF. Functional remodeling was investigated by echocardiography (after cardioversion to sinus rhythm). Structural remodeling was quantified by histological preparations with picrosirius red and immunohistochemical stainings. Results: A-TP resulted in decreased left ventricular ejection fraction (LVEF) accompanied by increased end-diastolic and end-systolic left atrium (LA) volume and area. In addition, A-TP was associated with mitral valve (MV) regurgitation, diastolic dysfunction and increased atrial and ventricular fibrotic extracellular matrix (ECM). Conclusions: A-TP induced AF with concomitant LV systolic and diastolic dysfunction, increased LA volume and area, and atrial and ventricular fibrosis.

The KCa2 Channel Inhibitor AP30663 Selectively Increases Atrial Refractoriness, Converts Vernakalant-Resistant Atrial Fibrillation and Prevents Its Reinduction in Conscious Pigs.

AIMS: To describe the effects of the KCa2 channel inhibitor AP30663 in pigs regarding tolerability, cardiac electrophysiology, pharmacokinetics, atrial functional selectivity, effectiveness in cardioversion of tachy-pacing induced vernakalant-resistant atrial fibrillation (AF), and prevention of reinduction of AF. METHODS AND RESULTS: Six healthy pigs with implanted pacemakers and equipped with a Holter monitor were used to compare the effects of increasing doses (0, 5, 10, 15, 20, and 25 mg/kg) of AP30663 on the right atrial effective refractory period (AERP) and on various ECG parameters, including the QT interval. Ten pigs with implanted neurostimulators were long-term atrially tachypaced (A-TP) until sustained vernakalant-resistant AF was present. 20 mg/kg AP30663 was tested to discover if it could successfully convert vernakalant-resistant AF to sinus rhythm (SR) and protect against reinduction of AF. Seven anesthetized pigs were used for pharmacokinetic experiments. Two pigs received an infusion of 20 mg/kg AP30663 over 60 min while five pigs received 5 mg/kg AP30663 over 30 min. Blood samples were collected before, during, and after infusion on AP30663. AP30663 was well-tolerated and prominently increased the AERP in pigs with little effect on ventricular repolarization. Furthermore, it converted A-TP induced AF that had become unresponsive to vernakalant, and it prevented reinduction of AF in pigs. Both a >30 ms increase of the AERP and conversion of AF occurred in different pigs at a free plasma concentration level of around 1.0-1.4 µM of AP30663, which was achieved at a dose level of 5 mg/kg. CONCLUSION: AP30663 has shown properties in animals that would be of clinical interest in man.

Role of baseline 12­lead ECG in predicting syncope caused by arrhythmia in patients investigated using an implantable loop recorder.

AIM: To evaluate the role of baseline 12­lead ECG in predicting the syncope mechanism during continuous monitoring using an implantable loop recorder (ILR). METHODS: Consecutive patients with syncope implanted with an ILR were enrolled. Baseline 12­lead ECG were related to ECG diagnosis derived from ILR tracings recorded at the time of syncope recurrence. RESULTS: In total 300 patients with a mean age of 66 ±â€¯16 years were included, 49% (146/300) received an ILR-guided diagnosis during follow-up. Patients with abnormal baseline ECG more frequently received an ILR-guided diagnosis compared to those with normal baseline ECG 59% vs. 44%, p = 0.018. For a diagnosis of arrhythmic syncope, the corresponding frequencies were 45% vs. 26%, p = 0.001.Patients with bifascicular block significantly more common received an ILR-guided diagnosis 76% (25/33) compared to those with normal baseline ECG 44% (90/205), p ≪ 0.001. In this subgroup, 96% (24/25) were diagnosed with arrhythmic syncope, 23 of which were due to bradyarrhythmia. Bifascicular block occurred almost exclusively among those ≥60 years (31/33). After logistic regression the adjusted OR for arrhythmic syncope was significant for bifascicular block 5.5 (95%CI 2.3-13.2), p ≪ 0.001. PPV for bifascicular block in predicting arrhythmic syncope was 73% and NPV 73%. CONCLUSION: A baseline 12­lead ECG with bifascicular block was a strong predictor for syncope during follow-up, most often due to bradyarrhythmia caused by intermittent complete heart block. No other ECG findings were associated with the ILR outcome. We find it reasonable to consider permanent pacing instead of an ILR for patients with bifascicular block and unexplained syncope.

Stroke incidence and anticoagulation treatment in patients with pacemaker-detected silent atrial fibrillation.

BACKGROUND: Silent atrial fibrillation (AF) episodes are common but the role of anticoagulation treatment is under debate. METHODS: Consecutive patients with dual-chamber pacemakers for sinus node disease or AV block/bundle branch block were retrospectively enrolled and the development of silent AF, any anticoagulation and the incidence of ischaemic stroke and dementia were recorded. RESULTS: In total 411 patients without and 267 with known AF at implant were included. During a median follow-up of 38 months, 30% (125/411) of patients without known AF at implant were diagnosed with silent AF, 62% of those had or were prescribed anticoagulation. Heart failure (p = 0.03) and age >75 years (p = 0.0002) were risk markers for incident silent AF. In patients with known AF at implant, 80% (216/267) were on anticoagulation at implant. The annual stroke incidence was 2.1% in patients with known AF at implant, as compared to 1.9% in patients who developed silent AF during follow-up, and 1.4% in patients without AF. Vascular dementia developed in 11.2% and 6.2% respectively in patients with known AF versus no AF (p = 0.048) as well as in 5.6% of those with silent AF (p = 0.09). CONCLUSION: The stroke risk in our study population with an incident silent AF diagnosis may have been significantly decreased by the high proportion of anticoagulation treatment. This could imply that without this treatment the stroke risk might have been high enough to justify anticoagulation. Development of vascular dementia was twice as common among patients with known AF as compared to those witht silent AF or no AF. More data is needed to inform the optimal treatment for these patients.

Patient-Reported Outcomes in Relation to Continuously Monitored Rhythm Before and During 2 Years After Atrial Fibrillation Ablation Using a Disease-Specific and a Generic Instrument.

BACKGROUND: Atrial fibrillation (AF) ablation improves patient-reported outcomes, irrespective of mode of intermittent rhythm monitoring. We evaluated the use of an AF-specific and a generic patient-reported outcomes instrument during continuous rhythm monitoring 2 years after AF ablation. METHODS AND RESULTS: Fifty-four patients completed the generic 36-Item Short-Form Health Survey and the AF-specific AF6 questionnaires before and 6, 12, and 24 months after AF ablation. All patients underwent continuous ECG monitoring via an implantable loop recorder. The generic patient-reported outcomes scores were compared with those of a Swedish age- and sex-matched population. After ablation, both summary scores reached normative levels at 24 months, while role-physical and vitality remained lower than norms. Responders to ablation (AF burden <0.5%) reached the norms in all individual 36-Item Short-Form Health Survey domains, while nonresponders (AF burden >0.5%) reached norms only in social functioning and mental component summary. All AF6 items and the sum score showed moderate to large improvement in both responders and nonresponders, although responders showed significantly greater improvement in all items except item 1 from before to 24 months after ablation. Higher AF burden was independently associated with poorer physical component summary and AF6 sum score. CONCLUSIONS: The AF-specific AF6 questionnaire was more sensitive to changes related to AF burden than the generic 36-Item Short-Form Health Survey. Patients improved as documented by both instruments, but a higher AF burden after ablation was associated with poorer AF-specific patient-reported outcomes and poorer generic physical but not mental health. Our results support the use of an AF-specific instrument, alone or in combination with a generic instrument, to assess the effect of ablation. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00697359.

Development and Validation of the AFImpact: An Atrial Fibrillation-Specific Measure of Patient-Reported Health-Related Quality of Life.

BACKGROUND: Improvement in health-related quality of life is a key therapeutic goal of disease management in atrial fibrillation (AF). OBJECTIVES: To describe the development of the AFImpact, an AF-specific health-related quality-of-life patient-reported outcome measure. METHODS: Development and validation of the AFImpact comprised a qualitative stage, consisting of a literature review and concept elicitation interviews (91 patients with AF), item generation, and cognitive debriefing (30 patients with AF), and a quantitative stage, consisting of evaluation of the instrument's psychometric properties (313 patients with AF). Preliminary responsiveness to change was assessed in 118 patients undergoing cardioversion. RESULTS: On the basis of the literature review and concept elicitation interviews, 75 items were generated. Factor analyses guided a reduction to 18 items. Three domains were confirmed: vitality (7 items), emotional distress (8 items), and sleep (3 items). The 18-item AFImpact demonstrated high item convergent and discriminant validity. Cronbach α coefficients showed high internal consistency reliability. Test-retest reliability of individual items in stable patients (n = 33) was satisfactory, with intraclass correlation coefficients ranging from 0.61 to 0.86. All three AFImpact domain scores differentiated patients who reported different levels of overall health, thereby supporting known-groups validity. Scores for each item improved after cardioversion, with effect sizes ranging from -0.19 to -0.65. CONCLUSIONS: Psychometric evaluations support the reliability and validity of the AFImpact as a patient-reported outcome instrument to measure the impact of AF, with preliminary results in patients undergoing cardioversion supporting responsiveness to change.

Patients without comorbidities at the time of diagnosis of atrial fibrillation: causes of death during long-term follow-up compared to matched controls.

BACKGROUND: Little is known about the long-term, cause-specific mortality risk in patients without comorbidities at the time of diagnosis of atrial fibrillation (AF). METHODS: From a nation-wide registry of patients hospitalized with incident AF between 1995 and 2008 we identified 9 519 patients with a first diagnosed AF and no comorbidities at the time of AF diagnosis. They were matched with 12 468 controls. The follow-up continued until December 2008. Causes of death were classified according to the ICD-10 codes. RESULTS: During follow-up, 11.1% of patients with AF and 8.3% of controls died. Cardiovascular diseases were the most common causes of death and the only diagnoses which showed significantly higher relative risk in patients with AF than controls (HR 2.0, 95% CI 1.8-2.3), and the relative risk was significantly higher in women than in men. Stroke was a more common cause among patients with AF, 13.1% versus 9.7% (HR 2.7, 95% CI 1.8-4.0), while cerebral hemorrhage was more common among controls, 4.7% versus 10.2% (HR 0.9, 95% CI 0.6-1.5). The time from AF diagnosis to death was 6.0 ± 3.1 years. CONCLUSIONS: In patients with incident AF and no known comorbidities at the time of AF diagnosis, only cardiovascular diseases were more often causes of death as compared to controls. Women carried a significantly higher relative risk than men.

Patients with atrial fibrillation and outcomes of cerebral infarction in those with treatment of warfarin versus no warfarin with references to CHA2DS2-VASc score, age and sex - A Swedish nationwide observational study with 48 433 patients.

AIMS: There is controversy in the guidelines as to whether patients with atrial fibrillation and a low risk of stroke should be treated with anticoagulation, especially those with a CHA2DS2-VASc score of 1 point. METHODS: In a retrospective, nationwide cohort study, we used the Swedish National Patient Registry, the National Prescribed Drugs Registry, the Swedish Registry of Education and the Population and Housing Census Registry. 48 433 patients were identified between 1 January 2006 and 31 December 2008 with incident atrial fibrillation who were divided in age categories, sex and a CHA2DS2-VASc score of 0, 1, 2 and ≥3 and they were included in a time-varying analysis of warfarin treatment versus no treatment. The primary end-point was cerebral infarction and stroke, and patients were followed until 31 December 2009. RESULTS: Patients with 1 point from the CHA2DS2-VASc score showed the following adjusted hazard ratios (HR) with a 95% confidence interval: men 65-74 years 0.46 (0.25-0.83), men <65 years 1.11 (0.56-2.23) and women <65 years 2.13 (0.94-4.82), where HR <1 indicates protection with warfarin. In patients <65 years and 2 points, HR in men was 0.35 (0.18-0.69) and in women 1.84 (0.86-3.94) while, in women with at least 3 points, HR was 0.31 (0.16-0.59). In patients 65-74 years and 2 points, HR in men was 0.37 (0.23-0.59) and in women 0.39 (0.21-0.73). Categories including age ≥65 years or ≥3 points showed a statistically significant protection from warfarin. CONCLUSIONS: Our results support that treatment with anticoagulation may be considered in all patients with an incident atrial fibrillation diagnosis and an age of 65 years and older, i.e. also when the CHA2DS2-VASc score is 1.

Assessment of Atrial Fibrillation-Specific Symptoms Before and 2 Years After Atrial Fibrillation Ablation: Do Patients and Physicians Differ in Their Perception of Symptom Relief?

OBJECTIVES: The aim of this study was to evaluate patient-reported and physician-assessed atrial fibrillation (AF)-related symptoms after AF ablation. BACKGROUND: Success of AF ablation is usually defined as freedom from AF, although symptom relief is often patients' desire. METHODS: Symptom relief was assessed as perceived by patients using the short, validated, AF-specific symptom questionnaire AF6 and as classified by physicians using the European Heart Rhythm Association (EHRA) classification at baseline and 6, 12, and 24 months after AF ablation. Recurrence of arrhythmia was documented by continuous electrocardiographic monitoring. RESULTS: In total, 54 patients completed the 24-month follow-up. All 6 items on the AF6, AF6 sum score, and EHRA class improved significantly over time. The greatest improvement was seen during the first 6 months after ablation, but AF6 scores showed continued improvement up to 12 months, in contrast to EHRA class. There was a low correlation between AF6 score and EHRA class, but the predictive ability was low. Both AF6 scores and EHRA class were significantly correlated with AF burden at all times after ablation. A change of >9 points in AF6 sum score corresponded to a meaningful reduction in symptom severity. CONCLUSION: Patient-reported and physician-assessed outcomes were both useful in assessing symptom relief after AF ablation, although patient-reported outcomes were more sensitive tools. There was also a discrepancy between patient-reported and physician-assessed outcomes after ablation. Freedom from AF and a low AF burden most often resulted in a reduction of symptoms, but symptom relief also occurred despite little effect on the arrhythmia.

In Silico Predictions and In Vivo Results of Drug-Drug Interactions by Ketoconazole and Verapamil on AZD1305, a Combined Ion Channel Blocker and a Sensitive CYP3A4 Substrate.

The objectives were to estimate and compare, in silico and in vivo, the effects of a strong and a moderate CYP3A4 inhibitor on AZD1305 pharmacokinetics. In silico, simulations were performed with the computer software Simcyp, and the predicted outcome was compared with the results observed in healthy male subjects. In silico, the geometric mean plasma exposure of AZD1305 + ketoconazole showed a 7.1-fold higher AUC and a 4.4-fold higher Cmax compared with AZD1305 alone. Coadministration with verapamil gave a 1.9-fold higher AUC and a 1.7-fold higher Cmax compared with AZD1305 alone. In vivo, the plasma exposure of AZD1305 + ketoconazole showed a 7.7-fold higher AUC and a 4.8 -fold higher Cmax compared with AZD1305 alone. Coadministration with verapamil gave a 2.2-fold higher AUC and a 2.0-fold higher Cmax compared with AZD1305 alone. The mean maximum QTcF increase from baseline was 407, 487, and 437 milliseconds for AZD1305, alone and in combination with verapamil or ketoconazole, respectively. Simcyp predicted the effects of ketoconazole and verapamil on the sensitive CYP3A4 substrate AZD1305 pharmacokinetics well. Both the in vivo study and the Simcyp predictions suggest a contraindication for strong CYP3A4 inhibitors and AZD1305 when given in combination.

Rhythm Control and Its Relation to Symptoms during the First Two Years after Radiofrequency Ablation for Atrial Fibrillation.

CLINICAL TRIAL REGISTRATION: URL: http://clinicaltrials.gov. Unique Identifier: NCT00697359. OBJECTIVES: To evaluate rhythm control up to two years after atrial fibrillation (AF) ablation and its relation to reported symptoms. BACKGROUND: The implantable loop recorder (ILR) continuously records the electrocardiogram (ECG), has an automatic AF detection algorithm, and has a possibility for patients to activate an ECG recording during symptoms. METHODS: Fifty-seven patients (mean age 57 ± 9 years, 60% male, 88% paroxysmal AF) underwent AF ablation following ILR implantation. Device data were downloaded at the ablation and three, six, 12, 18, and 24 months after ablation. RESULTS: Fifty-four patients completed the two-year follow-up. Thirteen (24%) patients had no AF episodes detected by ILR during follow-up. Ten of 41 patients (24%) with AF recurrence were only detected by ILR and AF recurrences were detected earlier by ILR (P < 0.001). The median AF burden in patients with AF recurrence was 5.7% (interquartile range 0.4-14.4) and was even lower in patients with AF only detected by ILR (P = 0.001). Forty-eight % of the patients indicated symptoms via the patient activator but 33% of those recordings were not due to AF. Early AF recurrence (within 3 months) was highly associated with later AF recurrence (P < 0.001). AF burden >0.5% and longest AF episode >6 hours before the ablation were independent predictors of AF recurrence during intermittent but not continuous monitoring. CONCLUSIONS: After AF ablation, the AF burden was low throughout the 24 months follow-up. Nevertheless, symptoms were commonly indicated but one-third of patient-activated recordings did not show AF. Continuous monitoring was superior to intermittent follow-up in detecting AF episodes and assessing the AF burden.

Inverse Correlation between the Atrial Fibrillatory Rate and the Ventricular Repolarization Time: Observations at Baseline and after an Intravenous Infusion of a Combined Potassium and Sodium Current Blocker.

BACKGROUND: The atrial fibrillatory rate (AFR) and the ventricular rate and repolarization (QTcF) were studied at baseline and under the influence of the combined potassium and sodium current blocker AZD7009. METHODS: Ninety-two patients with atrial fibrillation (AF) were randomized to an intravenous infusion of AZD7009 or placebo. The atrial fibrillatory activity in lead V1 was extracted using spatiotemporal QRST cancellation. The exponential decay (ED) characterized the degree of atrial signal organization. RESULTS: The mean (SD) AFR at baseline was 396  ±  57 (range 253-584) and 410 ± 33 (range 363-469) bpm in patients randomized to AZD7009 and placebo, respectively. The AFR decreased within the first minutes of the AZD7009 infusion and reached its minimum of 235 ± 34 bpm after 18 minutes. On placebo, the AFR was unchanged. On AZD7009, the ED decreased from 1.2 ± 0.3 to reach its lowest level at 0.7 ± 0.2 after 14 minutes. The ventricular rate did not change significantly over time. The AFR was statistically significantly related to the ventricular repolarization at baseline, the QTcF being longer at lower AFR values, and this relationship remained during and after AZD7009. In the full multivariate linear regression model, including age, sex, left ventricular ejection fraction, QRS duration, heart rate, QTcF, AF episode duration, AF history duration, and right atrial or left atrial size, only QTcF and age were statistically significantly correlated with the AFR. The correlation remained when the uncorrected QT interval was used. CONCLUSIONS: The QTcF was inversely correlated with AFR, both at baseline and during administration of AZD7009. The AFR was not correlated with the ventricular rate.