Ignite Creation Date:
2024-05-06 @ 9:19 AM
Last Modification Date:
2024-10-26 @ 12:12 PM
Study NCT ID:
NCT02955004
Status:
COMPLETED
Last Update Posted:
2019-09-17
First Post:
2015-09-17
Brief Title:
Electrical Cardioversion of Recent Onset Atrial Fibrillation - Silent Thromboembolic Events Reverse Atrial Remodeling
Sponsor:
Uppsala University Hospital
Organization:
Uppsala University Hospital
Study Overview
Official Title:
Electrical Cardioversion of Recent Onset Atrial Fibrillation - a Study of Silent Thromboembolic Events Reverse Atrial Electrical and Functional Remodeling Including Inflammatory Neurohormonal and Thromboembolic Biomarkers
Status:
COMPLETED
Status Verified Date:
2019-09
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
ECAF-STAR
Brief Summary:
The purpose of this study is to study the effects of transthoracic electrical cardioversion for restoration of sinus rhythm in patients who present with recent onset atrial fibrillation with regard to new silent cerebral thrombo-embolic lesions and cognitive function as well as electrical and functionalstructural reverse remodelling and its effects on inflammatory changes specific cardiac biomarkers vasoactive peptides coagulation activity and active fibrinolysis
Detailed Description:
Working plan This study will give information about the incidence of silent cerebral thrombo-embolic events in patients with recent onset AF a population which is expected to consist mostly of paroxysmal AF patients
Patients with atrial fibrillation AF duration less than 48 hours and fulfilling inclusion and not exclusion criteria will be included in the study by a cardiologist on the day of cardioversion and study nurse will be notified to plan for the investigations The patient will undergo clinical examination clinical history will be taken and blood sampling Once 12 lead ECG echocardiography questionnaires telemetry and MR have been done the patient will be electrically cardioverted After the cardioversion the patient will be subject to echocardiography of the heart again blood-sampling 12 lead ECG and MR brain The patient is discharged but will be studied by echocardiography of the heart and MR brain again on day 7 - 10 Thereafter the patient will be followed for 30 days - see flowchart
The day of cardioversion is defined as Day 0
31 ASSESSMENT OF REMODELINGREVERSE REMODELING 311 Electrical remodeling Standard 12-Lead electrocardiography ECG at every health care visit Day -1 Day 0 before and immediately after DCC Day 0 at discharge Day 7-10 and 30 Recorded with automatic analysis of intervals Paper speed 50 mmsec
O Data to be collected Rhythm heart rate P wave duration and amplitude
312 Functional remodeling Echocardiographic analysis - App 1 Left and right atrial dimensions and volumes 53 Global left atrial function left atrial ejection fraction assessed by 2D and speckle tracking 53 54 Left ventricular ejection fraction and left ventricular diastolic function transmitral velocities EE index53-56 O Echocardiographic data will be collected and stored in the routinely used database of the department of Clinical Physiology and as raw images in a separate database dedicated for the study in the care of the investigators for offline review and measurements The Core lab in Uppsala will do all analysis
O Time of collection prior to cardioversion within 24 h after cardioversion and at day 7 - 10 after cardioversion
313Neurohormonal - inflammatory indices cardiac biomarkers vasoactive peptides
High-sensitivity cardiac troponin T hsTnT and N-terminal pro-brain natriuretic peptide Nt-proBNP will be measured as sensitive and specific markers of cardiac injury strain filling pressures and B-type natriuretic peptide levels correlate with AF burden in patients with lone AF and is a strong predictor of recurrent arrhythmia after ablation A stable fragment of vasoactive peptide C-terminal -proendothelin-1 will be measured because of its relation recurrence of AF which may be a risk factor for embolism and because of its possible role in the pathogenesis and recurrence of AF and the association with atrial dilatation fibrosis and hypertrophy which may contribute to AF persistence and embolism C-Reactive protein CRP Interleukin-662-65 Routine blood tests Hb Platelets White blood cell count Na K Creatinine international normalized ratio INR thyroid-stimulating hormone TSH free-T4 only once before cardioversion
O Blood sampling test Day 0 before sample 1 and 4 1 hours after cardioversion at time for MRI no 2 before discharge sample 2 and day 7-10 sample 3 The core lab in Uppsala will do all analysis
32 RHYTHM MONITORING O Continuous ECG monitoring O During and after cardioversion to be printed from cardioverter or telemetry or 7 - 10 day Holter
O 7-day Holter monitoring To be initiated on Day 0 prior to cardioversion for 7 days The Core lab in Uppsala will do all analysis
12 lead ECG recording As above and at symptoms indicating recurrence of AF
Data to be collected
Time to first P-wave to assess sinus node recovery after DC and time for immediate recurrence of AF
AF burden defined as total time in AF during the first 7 days Time to first AF recurrence sustained AF duration 30 seconds during first 7 days then at first symptom of AF confirmed on ECG Number of sustained and non-sustained AF episodes during the first 7 days Mean median - range of duration of AF episodes during the first 7 Days
33 ASSESSMENT OF THROMBOEMBOLIC BIOMARKERS MENTAL TESTS AND CEREBRAL ISCHEMIC EVENTS
331 Biomarkers Coagulation activity by analysing plasma markers for thrombin activity P-selectin d-dimer and prothrombin fragment 12 von Willebrand factor antigen vWF-Ag and factor VIIIC
Active fibrinolysis plasmin-alpha 2-plasmin inhibitor complex PIC P-fibrinogen och P-Fibrin Platelet activity platelet factor 4 PF4 Brain damage markers S100 Blood sampling test as above
332 Neurological Cognitive assessment National Institute of Health Stroke Scale NIHSS Standardized assessment of neurological deficit66
To be performed Day 0 prior to cardioversion Day 7-10 Day 30 and when clinically evident cerebrovascular event
Mini-Mental-Test Mini Mental State Examination MMSE and Trail Making Test A och B TMT A och B To be performed Day 0 prior to cardioversion Day 7-10 Day 30 and if clinically evident cerebrovascular event
333 Brain magnetic resonance imaging MRI is performed for the assessment of silent thromboembolism which is defined as 2-3 mm or larger lesion with restricted diffusion on MRI with diffusion weighted sequence5171-75 Silent or clinically evident cerebrovascular events occurring during cardioversion will be detected and eventually not counted as late coming emboli in relation to reverse remodeling
To be performed Prior to and within 24 hours after DCC on Day 0 and on Day 7 - 10 after DCC
Data to be collected presence size number and vascular distribution of any focal abnormality consistent with embolic lesion
Technique for MRI without contrast injection
Sag T2 or T1 to position and obtain transversal slices with high reproducibility
DWI transversal 5 mm slices b0 och b1000 calculation of ADC maps usually automatic by scanner T2 tsefse transversal 5 mm slices T2 FLAIR transversal 5 mm slices
4 Statistical analysis sample size data handling This pilot study will give information about the incidence of silent cerebral thromboembolic events and associated clinical variables that may affect the outcome in patients with recent onset AF who are expected to mainly suffer from paroxysmal AF
Based on previous reports of patients undergoing MRI before and after AF ablations the of patients with chronic cerebral lesions detected on MRI at baseline varies widely from 4 to 79 with 10 being the most representative figure for patients with paroxysmal AF Previous observations have reported varying frequencies of new silent cerebral lesions on MRI after AF ablation 4-38 coronary angiography 10 and retrograde aortic catheterisation of patients with aortic valve stenosis 22 New asymptomatic cerebral ischemic lesions in patients undergoing AF ablation have been reported after the use of irrigated radiofrequency RF catheters 7-11 the most common routine ablation procedure and even a higher frequency of lesions 37 using a specialized circular RF ablation catheter Based on these observations the investigators argued that a 20 increase in incidence of new asymptomatic cerebral ischemic lesions in patients undergoing DC cardioversion would be clinically significant and warrant alternative routines for cardioversions
Determination of sample size Considering a 20 increase ie from 10 at baseline to 30 in incidence of silent cerebral lesions following electrical cardioversion the required number of patients to reject the null-hypothesis with 90 power and at the 005 significance level two-sided is 35 To allow for drop-outs 40 patients will be included in the study The sample size calculations were performed in the software nQuery Advisor version 70
It is reasonable to perform a pilot study of 40 patients in order to get an indication of the number of silent cerebral events A total of 70 patients will be screened to ensure that 40 patients will remain in sinus rhythm at least 7 days after cardioversion
Categorical variables will be reported as counts and percentages whereas continuous variables as means and standard deviations SD or medians and interquartile ranges as applicable
The relationship between clinical variables qualifying history duration of AF AF duration CHADS2VASC score biomarkers conversion to sinus rhythm left atrial function and left atrial volume confounding variables and incidence of new silent cerebral ischemic lesions at Day 1 and 7-10 post MR will be tested in a multiple logistic regression model using a stepwise selection procedure p005 The model will be validated using bootstrapping
The number of new silent cerebral ischemic lesions will be modelled as poisson or negative binomial regression models as applicable
Median concentrations of the biomarkers will be compared with baseline levels by nonparametric Wilcoxon rank-sum test or Kruskal- Wallis test when appropriate
The association between biomarker concentrations and new embolic lesion will be evaluated over a follow up period 7 -10 days The association between baseline concentration of each biomarker and new embolic lesion will be assessed by univariable Cox proportional hazards models Biomarkers will be modelled as continuous variables expressed as 1 SD increment as linearity of the hazard will be tested by appropriate transformation using restricted cubic splines to account for possible nonlinear relationships Cox multivariable models will be performed to evaluate the independent prognostic value of each biomarker separately adjusting for baseline covariates emerged as statistically significant from a stepwise selection procedure p 005 The investigators will also investigate whether the addition of different combinations of the biomarkers improve the discrimination of the model The independent prognostic value of each biomarker on new embolic lesion will be assessed by univariable and multivariable Cox models
Each biomarker measured at baseline Day 1 before and immediately after DCC at discharge after 7 - 10 days and 1 months will be analysed graphically over time at the patient level as well as by summary statistics
All probability values are two-tailed and 95 confidence intervals CIs will be calculated Because of the exploratory nature of this study adjustments for the multiplicity of statistical analyses will not be made
A 2-sided P-value 005 will be considered statistically significant
5 Clinical Significance It is of paramount importance to assess if electrical cardioversion performed within 48 hours after AF onset without preceding oral anticoagulation results in silent strokes as it is the present clinical routine and no scientific data is available
A 20 increase in incidence of new asymptomatic cerebral ischemic lesions in patients undergoing DC cardioversion is in this study defined as clinically significant If other cardioversion strategies can be identified that result in 10 lower incidence of events that figure may then be regarded as clinically significant
Patients with atrial fibrillation AF duration less than 48 hours and fulfilling inclusion and not exclusion criteria will be included in the study by a cardiologist on the day of cardioversion and study nurse will be notified to plan for the investigations The patient will undergo clinical examination clinical history will be taken and blood sampling Once 12 lead ECG echocardiography questionnaires telemetry and MR have been done the patient will be electrically cardioverted After the cardioversion the patient will be subject to echocardiography of the heart again blood-sampling 12 lead ECG and MR brain The patient is discharged but will be studied by echocardiography of the heart and MR brain again on day 7 - 10 Thereafter the patient will be followed for 30 days - see flowchart
The day of cardioversion is defined as Day 0
31 ASSESSMENT OF REMODELINGREVERSE REMODELING 311 Electrical remodeling Standard 12-Lead electrocardiography ECG at every health care visit Day -1 Day 0 before and immediately after DCC Day 0 at discharge Day 7-10 and 30 Recorded with automatic analysis of intervals Paper speed 50 mmsec
O Data to be collected Rhythm heart rate P wave duration and amplitude
312 Functional remodeling Echocardiographic analysis - App 1 Left and right atrial dimensions and volumes 53 Global left atrial function left atrial ejection fraction assessed by 2D and speckle tracking 53 54 Left ventricular ejection fraction and left ventricular diastolic function transmitral velocities EE index53-56 O Echocardiographic data will be collected and stored in the routinely used database of the department of Clinical Physiology and as raw images in a separate database dedicated for the study in the care of the investigators for offline review and measurements The Core lab in Uppsala will do all analysis
O Time of collection prior to cardioversion within 24 h after cardioversion and at day 7 - 10 after cardioversion
313Neurohormonal - inflammatory indices cardiac biomarkers vasoactive peptides
High-sensitivity cardiac troponin T hsTnT and N-terminal pro-brain natriuretic peptide Nt-proBNP will be measured as sensitive and specific markers of cardiac injury strain filling pressures and B-type natriuretic peptide levels correlate with AF burden in patients with lone AF and is a strong predictor of recurrent arrhythmia after ablation A stable fragment of vasoactive peptide C-terminal -proendothelin-1 will be measured because of its relation recurrence of AF which may be a risk factor for embolism and because of its possible role in the pathogenesis and recurrence of AF and the association with atrial dilatation fibrosis and hypertrophy which may contribute to AF persistence and embolism C-Reactive protein CRP Interleukin-662-65 Routine blood tests Hb Platelets White blood cell count Na K Creatinine international normalized ratio INR thyroid-stimulating hormone TSH free-T4 only once before cardioversion
O Blood sampling test Day 0 before sample 1 and 4 1 hours after cardioversion at time for MRI no 2 before discharge sample 2 and day 7-10 sample 3 The core lab in Uppsala will do all analysis
32 RHYTHM MONITORING O Continuous ECG monitoring O During and after cardioversion to be printed from cardioverter or telemetry or 7 - 10 day Holter
O 7-day Holter monitoring To be initiated on Day 0 prior to cardioversion for 7 days The Core lab in Uppsala will do all analysis
12 lead ECG recording As above and at symptoms indicating recurrence of AF
Data to be collected
Time to first P-wave to assess sinus node recovery after DC and time for immediate recurrence of AF
AF burden defined as total time in AF during the first 7 days Time to first AF recurrence sustained AF duration 30 seconds during first 7 days then at first symptom of AF confirmed on ECG Number of sustained and non-sustained AF episodes during the first 7 days Mean median - range of duration of AF episodes during the first 7 Days
33 ASSESSMENT OF THROMBOEMBOLIC BIOMARKERS MENTAL TESTS AND CEREBRAL ISCHEMIC EVENTS
331 Biomarkers Coagulation activity by analysing plasma markers for thrombin activity P-selectin d-dimer and prothrombin fragment 12 von Willebrand factor antigen vWF-Ag and factor VIIIC
Active fibrinolysis plasmin-alpha 2-plasmin inhibitor complex PIC P-fibrinogen och P-Fibrin Platelet activity platelet factor 4 PF4 Brain damage markers S100 Blood sampling test as above
332 Neurological Cognitive assessment National Institute of Health Stroke Scale NIHSS Standardized assessment of neurological deficit66
To be performed Day 0 prior to cardioversion Day 7-10 Day 30 and when clinically evident cerebrovascular event
Mini-Mental-Test Mini Mental State Examination MMSE and Trail Making Test A och B TMT A och B To be performed Day 0 prior to cardioversion Day 7-10 Day 30 and if clinically evident cerebrovascular event
333 Brain magnetic resonance imaging MRI is performed for the assessment of silent thromboembolism which is defined as 2-3 mm or larger lesion with restricted diffusion on MRI with diffusion weighted sequence5171-75 Silent or clinically evident cerebrovascular events occurring during cardioversion will be detected and eventually not counted as late coming emboli in relation to reverse remodeling
To be performed Prior to and within 24 hours after DCC on Day 0 and on Day 7 - 10 after DCC
Data to be collected presence size number and vascular distribution of any focal abnormality consistent with embolic lesion
Technique for MRI without contrast injection
Sag T2 or T1 to position and obtain transversal slices with high reproducibility
DWI transversal 5 mm slices b0 och b1000 calculation of ADC maps usually automatic by scanner T2 tsefse transversal 5 mm slices T2 FLAIR transversal 5 mm slices
4 Statistical analysis sample size data handling This pilot study will give information about the incidence of silent cerebral thromboembolic events and associated clinical variables that may affect the outcome in patients with recent onset AF who are expected to mainly suffer from paroxysmal AF
Based on previous reports of patients undergoing MRI before and after AF ablations the of patients with chronic cerebral lesions detected on MRI at baseline varies widely from 4 to 79 with 10 being the most representative figure for patients with paroxysmal AF Previous observations have reported varying frequencies of new silent cerebral lesions on MRI after AF ablation 4-38 coronary angiography 10 and retrograde aortic catheterisation of patients with aortic valve stenosis 22 New asymptomatic cerebral ischemic lesions in patients undergoing AF ablation have been reported after the use of irrigated radiofrequency RF catheters 7-11 the most common routine ablation procedure and even a higher frequency of lesions 37 using a specialized circular RF ablation catheter Based on these observations the investigators argued that a 20 increase in incidence of new asymptomatic cerebral ischemic lesions in patients undergoing DC cardioversion would be clinically significant and warrant alternative routines for cardioversions
Determination of sample size Considering a 20 increase ie from 10 at baseline to 30 in incidence of silent cerebral lesions following electrical cardioversion the required number of patients to reject the null-hypothesis with 90 power and at the 005 significance level two-sided is 35 To allow for drop-outs 40 patients will be included in the study The sample size calculations were performed in the software nQuery Advisor version 70
It is reasonable to perform a pilot study of 40 patients in order to get an indication of the number of silent cerebral events A total of 70 patients will be screened to ensure that 40 patients will remain in sinus rhythm at least 7 days after cardioversion
Categorical variables will be reported as counts and percentages whereas continuous variables as means and standard deviations SD or medians and interquartile ranges as applicable
The relationship between clinical variables qualifying history duration of AF AF duration CHADS2VASC score biomarkers conversion to sinus rhythm left atrial function and left atrial volume confounding variables and incidence of new silent cerebral ischemic lesions at Day 1 and 7-10 post MR will be tested in a multiple logistic regression model using a stepwise selection procedure p005 The model will be validated using bootstrapping
The number of new silent cerebral ischemic lesions will be modelled as poisson or negative binomial regression models as applicable
Median concentrations of the biomarkers will be compared with baseline levels by nonparametric Wilcoxon rank-sum test or Kruskal- Wallis test when appropriate
The association between biomarker concentrations and new embolic lesion will be evaluated over a follow up period 7 -10 days The association between baseline concentration of each biomarker and new embolic lesion will be assessed by univariable Cox proportional hazards models Biomarkers will be modelled as continuous variables expressed as 1 SD increment as linearity of the hazard will be tested by appropriate transformation using restricted cubic splines to account for possible nonlinear relationships Cox multivariable models will be performed to evaluate the independent prognostic value of each biomarker separately adjusting for baseline covariates emerged as statistically significant from a stepwise selection procedure p 005 The investigators will also investigate whether the addition of different combinations of the biomarkers improve the discrimination of the model The independent prognostic value of each biomarker on new embolic lesion will be assessed by univariable and multivariable Cox models
Each biomarker measured at baseline Day 1 before and immediately after DCC at discharge after 7 - 10 days and 1 months will be analysed graphically over time at the patient level as well as by summary statistics
All probability values are two-tailed and 95 confidence intervals CIs will be calculated Because of the exploratory nature of this study adjustments for the multiplicity of statistical analyses will not be made
A 2-sided P-value 005 will be considered statistically significant
5 Clinical Significance It is of paramount importance to assess if electrical cardioversion performed within 48 hours after AF onset without preceding oral anticoagulation results in silent strokes as it is the present clinical routine and no scientific data is available
A 20 increase in incidence of new asymptomatic cerebral ischemic lesions in patients undergoing DC cardioversion is in this study defined as clinically significant If other cardioversion strategies can be identified that result in 10 lower incidence of events that figure may then be regarded as clinically significant
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None