Study design
This trial is a prospective, observational, investigator-initiated, multi-center study to investigate the prevalence of and the time to recovery from AIC. A further aim is to identify potential predictors of AIC in patients with newly diagnosed and otherwise unexplained LVSD defined as left ventricular ejection fraction (LVEF) of < 50% and coexisting persistent tachyarrhythmia (AFib or AFlut with a HR > 100/min). The hallmark of AIC is reversibility of LVSD over time after rhythm restoration. Thus, the diagnosis ‘AIC’ is made ex juvantibus, so that patient groups are generated at the end of follow-up (6 months after rhythm control). If patients have recovered from LVSD, they are assigned to the AIC group; if not, they are assigned to the non-AIC group as comparator. Recovery is defined as an increase in LVEF of either ≥ 15% or ≥ 10% with an absolute EF of ≥ 50%. The flow diagram is presented in Fig. 1, and the SPIRIT Checklist is provided in Supplemental file 1.
Study objectives and endpoints
Primary endpoints (dual endpoint): The primary endpoint is a combination of a) the prevalence of AIC, i.e. the percentage of patients recovering from LVSD after rhythm restoration (from AFib or AFlut to sinus rhythm) and b) the time required to recover from LVSD.
Secondary endpoints: Prespecified secondary endpoints to identify possible predictive factors are geometric (LV end-diastolic diameter, LV end-systolic diameter and LA area) and functional parameters (grade of mitral regurgitation [MR]), biomarkers (Nterminal-pro hormone brain natriuretic peptide [NT-proBNP] and high-sensitive troponin T [hs-cTnT]), left ventricular late gadolinium enhancement (LGE), quality of life (QoL) and NYHA class. Geometric and functional parameters are measured by means of transthoracic echocardiography, biomarkers are measured in peripheral blood samples and LGE is quantified in a semi-automated analysis of cardiac magnetic resonance images (cMRI). A detailed methodological description of echocardiography and cMRI is provided in Supplemental file 2.
For calculation of the primary endpoint, LVEF at the initial stay and during the follow-up visits is measured via transthoracic echocardiography in the apical four and two chamber view. Group assignment is conducted as described above; the mean time to recovery either is given as the prevalence of AIC at the time of the follow-up visits 2, 4 and 6 months after rhythm restoration or is calculated for each patient from the time point of rhythm restoration to recovery by analyzing the successive echocardiographic studies within the follow-up.
Eligibility Criteria
Patients presenting with persistent tachycardic AFib or AFlut with a HR > 100/min and newly diagnosed and otherwise unexplained LVSD defined as left ventricular ejection fraction (LVEF) of < 50% are enrolled in this study. The patients need to be able and willing to follow the treatment according to current guidelines. [7, 12–15]
The inclusion criteria are as follows: (1) newly diagnosed LVEF < 50%, (2) persistent AFib or AFlut, (3) heart rate > 100 beats/min, (4) age ≥ 18 years and (5) signed, written consent.
The exclusion criteria are as follows: (1) valvular heart disease, (2) permanent AFib, (3) suspicion of accumulative disease or myocarditis, (4) inability to receive coronary angiography, (5) relevant coronary stenosis in the current coronary angiography, (6) percutaneous coronary intervention (PCI) or any other revascularization procedure in the past 3 months, (7) inability to participate in the follow-up visits, (8) life expectancy < 1 year, (9) recurrent arrhythmia during follow-up and (10) development of other diseases during follow-up that could potentially worsen left ventricular function.
Recruitment and screening
Patients with LVSD and tachyarrhythmia are screened in the emergency room and the cardiologic clinics at the University Hospital Regensburg, the Caritas Hospital St. Josef Regensburg and the University Hospital Leipzig (Germany). The presence of tachycardic AFib or AFlut is verified with 12-channel electrocardiography, and LVSD is determined with transthoracic echocardiography after initial rate control. Patient history is evaluated and screened for prior LVSD, which is an exclusion criterion if not explainable by prior arrhythmia. The history of PCI/revascularization and underlying arrhythmia is documented, and corresponding documents are requested, if needed. Rhythm restoration follows local clinical pathways. The patient receives coronary angiography and revascularization, if indicated [16]. Only patients without current or prior (3 months) PCI/revascularization are eligible. Inclusion and exclusion criteria are checked (except the last 2 exclusion criterions (no. 9, 10), which cannot be checked before the end of follow-up). The patient is informed about the study and consent is obtained, if applicable. See Supplemental files 3 and 4 for the forms given to the patients. Because of the observational design of the study, no randomization is needed.
Who Takes Informed Consent?
Signed, written informed consent is taken after a trained physician has explained the study’s background, aims and process (including follow-up visits) and has addressed any questions.
Study Treatment
In this observational study, patient treatment follows current guidelines for AFib and HF. [7, 12–15] Groups are assigned after the follow-up period. The procedure for rhythm restoration is the responsibility of the respective local cardiologic center. Treatment options are electrical cardioversion (ECV), pharmacological cardioversion or electrophysiological ablation therapy. In addition, therapeutic strategies can be combined and long-term antiarrhythmic therapy is an option. A detailed description of these procedures is given in Supplemental file 5. Of interest is the medical therapy for HF, which is individually optimized in respect of contraindications until reaching the maximum dose or the onset of side effects as recommended in current guidelines. [13]
Strategies for improving adherence to interventions
Rhythm control strategies may last a few minutes, in the case of ECV, or several hours, in the case of pulmonary vein isolation. Medication for HF is optimized during the initial hospital stay and adapted during follow-up. Attention is paid to potential side effects that may negatively affect adherence. The total trial duration is set at 6 months so that participation in the trial will not be too stressful for the patients. All patients are instructed to consult the study team if any problems occur that may be related to or interfere with the cardiovascular system and, in particular, if any heart rhythm disorders are suspected.
Relevant concomitant care permitted or prohibited during the trial
In case of recurrent arrhythmia or any other disease that may potentially worsen left ventricular function, the patient needs to be excluded from analysis.
Data Collection And Management
Data collection
The following data are collected during the initial hospital stay and the follow-up visits: LVEF, left ventricular end-systolic diameter (LVESD) and left ventricular end-diastolic diameter (LVEDD); left atrial (LA) size and the grade of MR are obtained by means of echocardiography. hs-TnT and NT-proBNP are measured in peripheral blood samples, the NYHA class is estimated by means of anamnesis and QoL is assessed with a questionnaire (Minnesota Living with HF Questionnaire). LGE is quantified once. Table 1 lists the timing of the diagnostic procedures. Echocardiographic images are collected and interpreted by an experienced cardiologist, and all cMRI/LGE image data are sent to the core lab and analysed by two experienced radiologists.
Table 1
| Initial stay | Visit 1 (2 months after RC) | Visit 2 (4 months after RC) | Visit 3 (6 months after RC) |
ECG (heart rate and rhythm) | X | X | X | X |
Echocardiography (LVEF, LVESD, LVEDD, MR, LA size) | X | X | X | X |
Lab values (NT-proBNP, hs-TnT) | X | X | X | X |
NYHA class (grade) | X | X | X | X |
QoL questionnaire* | X | X | X | X |
cMRI (LGE) | X** | | | |
ECG, echocardiography; cMRI, cardiac magnetic resonance imaging; hs-TnT, high-sensitive Troponin T; LVEF, left ventricular ejection fraction; LA, left atrial; LVEDD, left ventricular end-diastolic diameter; LVESD, left ventricular end-systolic diameter; NT-proBNP, N-terminal-pro hormone natriuretic peptide; LGE, late gadolinium enhancement; MR, mitral regurgitation; NYHA, New York Heart Association; QoL, quality of life; RC, rhythm control. * provided in Supplemental file 6. ** If cMRI cannot be scheduled within the hospital stay, a timely appointment is made after discharge.
Data management and confidentiality
Data are documented using Microsoft Excel spreadsheets and merged by C.S., T.K. and B.H. at the University of Regensburg. Personal patient data are stored in a password-protected file (master file) on a password-protected personal computer (PC) in a locked room at the University Hospital Regensburg. Personal information of participants including the name, residency and contact information is only collected after signed consent. Each patient is assigned a sequential study number (pseudonymous ID). This number is used as an identifier in a second file (working file), in which the above data are collected. The file is stored on a separate PC. For data exchange, a version of the second file is transmitted safely via UKR-Box (https://ukrbox.ukr.de/) or personally with a USB drive. The master file will be archived for 25 years according to the Clinical Trials Regulation. Because of the observational design of the study, no data monitoring committee is required.
Statistical Considerations
The study is designed and powered to allow estimation of the prevalence of AIC and to calculate the time to recovery from LVSD. For sample size calculation we considered a mean difference in LVEF of > 15% at 6 month of follow-up and a AFib/AFlut recurrence rate of 35% after rhythm control based on previous data. [17–19] Taking into account the estimated recurrence rate and applying an additional dropout rate of 5%, a total sample size of at least 64 patients was required for inclusion. The prevalence of AIC is calculated by dividing the number of patients with AIC by the total number of analysed patients. The time to recovery is assessed by calculating the prevalence for each visit; additionally, a mathematical model (curve-fit) will be employed to calculate recovery using the data collected during the visits. Secondary endpoints are calculated by ANOVA (or mixed model) analysis as well as univariate and multivariate logistic regression modelling.
Handling of missing data
Missing data of key parameters (endpoints) at baseline and at the end of follow-up (study visit at month 6) are not acceptable and lead to the exclusion of the participant from analysis. For the visits 2 and 4 months after rhythm restoration, missing data of < 5% of the participants are acceptable.
Standard protocol items: recommendations for interventional trials (SPIRIT)
This protocol was developed according to the SPIRIT guidelines. The SPIRIT checklist is available in Supplemental file 1.
Dissemination policy and plans for communicating important protocol amendments to relevant parties (e.g., trial participants, ethics committees)
Any intended modification to the protocol will be submitted to the responsible Ethics Committee. If approved, modifications will be communicated to the participants.