Background and Objective
With the increasing longevity and prevalence of cardiovascular disease, such as hypertension, the incidence of atrial fibrillation is rising continuously. A recent systematic review of 184 population studies showed that in 2010 the prevalence of atrial fibrillation was 596.2 per 100,000 (0.5962%) in men and 373.1 per 100,000 (0.3731%) in women, and the incidence per year was 77.5 per 100,000 (0.0775%) men and 59.5 per 100,000 (0.0595%) women [1]. There are therefore about 33.5 million patients with atrial fibrillation worldwide. According to these estimations [1] and the estimation of a 0.65% prevalence of persistent atrial fibrillation in adult Chinese [2], there are about 7 million patients with atrial fibrillation in China. However, this may be an underestimate for China as in many other countries [3].
In addition to the serious negative influence on quality of life, the main detrimental effect of atrial fibrillation is its complication of stroke. In 1978, when warfarin had not been recommended for management of atrial fibrillation as an anticoagulant therapy, the Framingham study showed that the risk of stroke was five-fold and 17-fold higher in the presence of nonvalvular and valvular atrial fibrillation respectively [4]. In the past few decades, with the substantial increase in the use of anticoagulant therapy in patients with atrial fibrillation, the incidence of stroke has decreased significantly. However, atrial fibrillation remains an important risk factor for ischemic stroke. A recent large stroke survey found that atrial fibrillation was responsible for about one-third of all strokes [5]. In China, very few patients with atrial fibrillation receive anticoagulant therapy, and hence the risk of stroke is high [2, 6]. Our recent study in an elderly Chinese population living in a suburb town of Shanghai showed that stroke mortality increased 5.3 times in patients with atrial fibrillation diagnosed according to one rest 12-lead electrocardiogram (ECG), while less than 1% of these patients received anticoagulant therapy [7].
One of the major reasons for the ineffective management of atrial fibrillation is the low awareness, especially the low diagnosis rate of new atrial fibrillation. Failure in the diagnosis and management of atrial fibrillation before the incidence of stroke leads to high mortality and disability. It is therefore imperative to diagnose and manage atrial fibrillation in a timely and effective fashion and prevent the complications of atrial fibrillation by screening, followed by the use of proven therapy, such as warfarin therapy. An automated handheld ECG system based on a smartphone has recently become available for the screening of atrial fibrillation in high-risk people, such as elderly or indigenous populations [8, 9]. The system works with a miniaturized ECG device attached to the back of a smartphone. The ECG signal is automatically transmitted to an application built into the smartphone and can then be analyzed for the presence of atrial fibrillation either with a cloud-based computing system or more recently with use of a validated algorithm on the smartphone as well [10], which provides an immediate diagnosis on the device. However, how this system can be most effectively used for the widespread screening of atrial fibrillation remains a question that requires investigation. Moreover, while repeated recordings will have a higher yield of atrial fibrillation diagnosis [11], it is not certain what constitutes an optimum number of ECG recordings balancing cost and effectiveness.
The present study was therefore designed as a randomized controlled trial to investigate whether more frequent ECG recordings and analyses with this automated ECG analysis system would significantly improve detection of atrial fibrillation compared with a single annual ECG screen in elderly Chinese population in a community health center.
General Design
The study is a 12-month randomized controlled trial that compares intensive ECG screening with usual ECG screening in the detection of atrial fibrillation in community health centers in Shanghai. Eligible participants will be randomized in a 1:1 ratio into intensive and usual screening groups, and within the intensive screening group in a 3:1 ratio into intensive and more intensive screening subgroups. ECG recordings and analyses will be performed annually in the usual screening group (baseline plus one recording at 12 months of follow-up), quarterly in the intensive screening group (baseline plus four recordings in 12 months of follow-up), and quarterly plus weekly in the first month after randomization in the more intensive screening group (baseline plus eight recordings in 12 months of follow-up). Figure 1 shows a flowchart of the study design.
Study Population
Men and women aged at least 65 years will be recruited from several community health centers in the city of Shanghai. Eligible patients should meet the following inclusion and exclusion criteria:
Inclusion criteria:
Age 65 years or older
Absence of atrial fibrillation at the baseline
Willing to visit and capable of visiting the outpatient clinic on his/her own for long-term follow-up.
Exclusion criteria:
Procedures at the Baseline and During Follow-Up
At the screening visit a questionnaire will be used to collect information on medical history, lifestyle, and use of medications, with the focus on the history of atrial fibrillation. If a participant has a history of atrial fibrillation, he/she will be excluded from randomization after information on the management of atrial fibrillation has been collected. Regardless of whether atrial fibrillation is present or not, the following physical examinations will be performed: body height, body weight, waist and hip circumferences, blood pressure, and heart rate.
An automated ECG analysis system (AliveCor® heart monitor) [9, 10] will be used to perform ECG recordings and analysis for the immediate diagnosis of atrial fibrillation according to the following timeframe:
Usual screening group: ECG recordings at the baseline plus at 1 year of follow-up; two ECG recordings in total.
Intensive screening subgroup: ECG recordings at the baseline plus quarterly during follow-up, at months 3, 6, 9, and 12; five ECG recordings in total.
More intensive screening subgroup: ECG recordings at the baseline plus weekly during the first month of follow-up and quarterly afterwards, at weeks 1, 2, 3, and 4 and months 3, 6, 9, and 12; nine ECG recordings in total.
All detected cases of atrial fibrillation will be further evaluated with a regular 12-lead ECG, and then referred to a specialist center for treatment.
At 1 year of follow-up, a follow-up questionnaire will be administered and physical examinations will be performed. All adverse events and serious adverse events will be recorded. Information about symptoms, severity, intervention, and outcome will be documented for all adverse events.
Outcome Evaluations
The outcome measure is the detection rate of atrial fibrillation in the usual and intensive screening groups. The primary comparison is between the usual screening group and the intensive screening group. The hypothesis is that the detection rate of atrial fibrillation would be 50% higher in the intensive screening group than in usual screening group. An exploratory comparison will be between the intensive screening subgroup (ECG recordings quarterly) and the more intensive screening subgroup (ECG recordings quarterly plus weekly in the first month after randomization) within the intensive screening group.
Physical Examinations
Anthropometric measurements will be performed by trained technicians. Body height will be measured to the nearest 0.5 cm, and body weight will be measured with light indoor clothes and without shoes. Waist and hip circumferences will be measured to the nearest 0.5 cm at the narrowest part of the torso and the widest portion of the buttocks respectively. Body mass index will be calculated as body weight in kilograms divided by the body height in meters squared and for the definition of overweight and obesity (body mass index ≥25 kg/m²).
Blood pressure will be measured three times consecutively by experienced physicians using a validated Omron 7051 oscillometric blood pressure monitor (Omron, Kyoto, Japan) after the participants have rested for at least 5 min in the sitting position. These three blood pressure readings will be averaged for the definition of hypertension (systolic ≥140 mmHg or diastolic ≥90 mmHg, or the use of antihypertensive medication).
Sample Size Estimation
The prevalence of atrial fibrillation as detected by an annual single 12-lead ECG was 2.5% in elderly people living in Shanghai [7]. Of those elderly people with atrial fibrillation, only 20% were aware of atrial fibrillation and 80% were unaware of atrial fibrillation [7]. The rate of atrial fibrillation newly detected by an ECG recording in 12 months could therefore be estimated to be 2.0% in elderly people without atrial fibrillation or without awareness of atrial fibrillation. Because there is no published study on intensive screening of atrial fibrillation in China, we have to refer to the data from a cluster randomized trial conducted in the United Kingdom for the improvement in the detection of atrial fibrillation by screening [12]. In that study, systematic screening (invitation for ECG) or opportunistic screening (pulse taking and invitation for ECG if the pulse was irregular) increased the detection rate of atrial fibrillation by 57%, from 1.04 to 1.63% [12]. We therefore hypothesize that the detection rate could be improved by 50% with more frequent ECG recordings. If a=0.05, a power of 80%, and a one-sided test are assumed, and a 1:1 ratio is used to assign patients to usual and intensive ECG screening, the study will require a sample size of 3013 participants per group. In consideration of a 15% superaddition, 3500 eligible participants per group should be enrolled. The more intensive ECG screening is exploratory within the intensive ECG screening group. The sample size of this subgroup was arbitrarily defined as 875 (i.e., one-fourth of the total number of participants in the intensive ECG screening group). Thus the number of patients required will be 3500, 2625, and 875 in the usual, intensive, and more intensive screening groups respectively, and 7000 for the whole trial.
Statistical Analysis
SAS version 9.2 (SAS Institute, Cary, NC, USA) will be used for data management and statistical analysis. The intention-to-treat principle will be followed in statistical analysis, which will be performed for all randomized patients who have at least one ECG recording during follow-up. Means and proportions at the baseline will be compared by the Student t-test and the c2-test respectively. The detection rate of atrial fibrillation and the incidence rate of adverse events will be compared between the study groups by the chi-square test and logistic regression in unadjusted and adjusted analyses respectively. Predefined subgroup analyses will be performed according to sex, age (65–74 years vs. ≥75 years), and the presence of overweight and obesity or hypertension.
Ethics
The study protocol was approved by the Ethics Committee of Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China. Informed written consent will be obtained from all study participants at the screening clinic visit.
Study Management
This study will be coordinated by the Center for Epidemiological Studies and Clinical Trials, Shanghai Institute of Hypertension, Department of Hypertension, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China. The recruitment and follow-up of patients will be done by physicians from the local community health centers. At the beginning of the study, these community physicians will be trained in the study protocol, including all procedures, such as the questionnaire, physical examinations, and ECG recordings. Study monitors independent of these community health centers will regularly visit these centers and check the accuracy of data for quality assurance.
Conclusions
The trial will provide evidence on the clinical effectiveness of more frequent ECG recordings by a handheld automated analysis system in the detection of atrial fibrillation. If proved effective, intensive screening by more frequent ECG recordings might have to be considered in people at high risk of atrial fibrillation. Otherwise, for instance, because inadequate power of the trial, an extended follow-up with an even more intensive screening approach may be considered to increase the detection rate of atrial fibrillation.