Pragmatic Randomized Clinical Trial of Early Dronedarone Versus Usual Care to Change and Improve Outcomes in Persons With First-Detected Atrial Fibrillation
试验速览
- 阶段
- 4 期
- 状态
- 已完成
- 入组人数
- 339
- 试验地点
- 102
- 主要终点
- Cardiovascular Hospitalization or Death
研究概览
简要总结
While there are several completed clinical trials that address treatment strategy in patients with symptomatic and recurrent AF, there are no randomized clinical trials that address treatment for first-detected AF. In usual care, these patients are started on an atrioventricular nodal blocking agent (beta-blocker or non-dihydropyridine calcium channel blocker) along with stroke prevention therapy. The investigators hypothesize that earlier administration of a well-tolerated antiarrhythmic drug proven to reduce hospitalization may result in improved cardiovascular outcomes and quality of life in patients first-detected AF.
The purpose of this study is to determine if treatment with dronedarone on top of usual care is superior to usual care alone for the prevention of cardiovascular hospitalization or death from any cause in patients hospitalized with first-detected AF. All patients will be treated with guideline-recommended stroke prevention therapy according to the CHA2DS2-VASc score. The treatment follow-up period will be 12 months. There will be two follow-up visits. Consistent with the pragmatic nature of the trial, the first follow-up will occur between 3 -9 months and the 2nd will occur at 12 months (with a window of +/- 30 days). Approximately 3000 patients will be enrolled and randomly assigned (1:1) to study intervention. The study intervention will be dronedarone 400 mg twice daily in addition to usual care versus usual care alone.
详细描述
Atrial fibrillation (AF) is the most common sustained arrhythmia encountered in clinical practice, accounting for one-third of arrhythmia-related hospitalizations.1 As many as 1 in 4 people develop AF over their lifetime after the age of 40 years. The prevalence and burden of AF in the United States is substantial; the age-adjusted incidence and prevalence has increased over the last 3 decades. Moreover, the number of Americans with AF is expected to increase 150% by 2050. The goals of care in the treatment of AF include (1) the management and reduction of risk factors, (2) prevention of tachycardia (rate control), (3) prevention of stroke, and (4) improvement of symptoms. Reduction or elimination of symptoms often requires rhythm control. Historically, randomized clinical trials have not demonstrated a mortality or stroke benefit with a rhythm control versus a rate control strategy.
Despite the failure of prior randomized clinical trials to demonstrate the superiority of rhythm control, the recent Early Treatment of Atrial Fibrillation for Stroke Prevention 4 (EAST-AFNET 4) trial demonstrated that early introduction of a comprehensive rhythm-control strategy (within one year of diagnosis) is superior to guideline-based usual care in improving cardiovascular (CV) outcomes at a mean follow-up of 5 years. The EAST-AFNET 4 trial found that early rhythm control reduced the primary outcome of CV death, stroke, hospitalization for heart failure (HF), or acute coronary syndrome (HR 0.79, 96% confidence interval (CI) 0.66-0.94, p = 0.005). EAST-AFNET 4 also demonstrated a reduction in the risk of stroke with early introduction of rhythm control (HR 0.65, 95% CI 0.44-0.98), a finding that was also observed with dronedarone in the ATHENA trial. In addition, maintenance of sinus rhythm has been associated with improved quality of life and increased exercise capacity in some patients. Outside of clinical trials, a quality-of-life study from the Registry on Cardiac Rhythm Disorders Assessing the Control of Atrial Fibrillation (RECORD-AF) found that rhythm control was associated with better quality of life.
There are several antiarrhythmic drugs (AADs) available for rhythm control of AF. Class I antiarrhythmic agents are predominantly limited to younger patients without coronary artery or structural heart disease. Patients with advanced chronic kidney disease, prolonged QT intervals, and/or severe left ventricular hypertrophy should not be treated with sotalol or dofetilide. Even when sotalol or dofetilide can be used, patients are often hesitant to start a medication that requires an inpatient hospitalization for drug loading and laboratory evaluation every 3 months. Amiodarone has been shown to be the most effective AAD for maintaining sinus rhythm in patients with AF; however, based on its side effect profile, amiodarone is only recommended as a first-line agent under specific clinical circumstances. Moreover, despite its efficacy, amiodarone has high rates of discontinuation due to frequent adverse events. In addition to its unfavorable side effects, several studies, including those of patients at risk for sudden cardiac death, have demonstrated an association between amiodarone use and higher mortality, as well as lower functional status. In contrast to amiodarone, dronedarone is a much better tolerated antiarrhythmic medication. In randomized controlled trials, dronedarone has been shown to prevent recurrent AF, improve rate control, and decrease cardiovascular hospitalization in patients with AF.
While there are several completed clinical trials that address treatment strategy in patients with symptomatic and recurrent AF, there are no randomized clinical trials that address treatment for first-detected or new-onset AF. After appropriate evaluation for oral anticoagulation, these patients are often started on an atrioventricular nodal blocking agent (beta-blocker or non-dihydropyridine calcium channel blocker). The investigators hypothesize that earlier administration of a well-tolerated antiarrhythmic drug proven to reduce hospitalization may result in improved quality of life and cardiovascular outcomes in patients with first-detected AF.
Risk Assessment:
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 21 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age >=21 years.
- •First-detected atrial fibrillation (defined as atrial fibrillation diagnosed in the previous 120 days).
- •Electrocardiographic documentation of atrial fibrillation.
- •Estimated life expectancy of at least 1 year.
- •Patient or legal authorized representative capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
排除标准
- •Patients with prior or planned treatment with rhythm control, either catheter ablation or chronic (>7 days) antiarrhythmic drug therapy.
- •Planned cardiothoracic surgery.
- •New York Heart Association class III or IV heart failure or a hospitalization for heart failure in the last 4 weeks.
- •Patients with reduced ejection fraction (LVEF ≤40%).
- •Permanent atrial fibrillation.
- •Ineligible for oral anticoagulation, unless CHA2DS2-VASc is less than 3 in women or 2 in men.
- •Bradycardia with a resting heart rate < 50 bpm
- •PR interval >280 msec or 2nd degree or 3rd degree atrioventricular block without a permanent pacemaker/cardiac implanted electronic device.
- •Corrected QT interval >=500 msec.
- •Pregnancy or breast feeding.
- •Severe hepatic impairment in the opinion of the investigator.
研究组 & 干预措施
Dronedarone
In most patients, the investigators anticipate usual care to include an atrioventricular nodal blocking agent (beta-blocker, non-dihydropyridine calcium channel blocker, or digoxin) without an antiarrhythmic. As dronedarone has anti-adrenergic rate controlling properties, a low dose of beta-blocker or calcium-channel blocker is recommended in the United States Prescribing Information (USPI) when starting dronedarone. In the dronedarone arm concomitant digoxin use will be contraindicated due to P-gp interaction based upon data from the PALLAS trial. All patients will receive oral anticoagulation for stroke prevention according to current guideline recommendations.
干预措施: Dronedarone (Drug)
结局指标
主要结局
Cardiovascular Hospitalization or Death
时间窗: Evaluated through 12 months from randomization
First occurrence of unplanned CV hospitalization or death from any cause within 12 months of randomization. All unplanned hospitalizations (i.e. admission with an overnight stay in an acute care healthcare facility/hospital) for cardiovascular causes will be considered a cardiovascular hospitalization.
次要结局
- Hospitalization for acute coronary syndrome(Evaluated through 12 months from randomization)
- Ischemic stroke or systemic embolism(Evaluated through 12 months from randomization)
- Hospitalization for new/worsening diagnosis of heart failure(Evaluated through 12 months from randomization)
- Time to first unplanned cardiovascular hospitalization(Evaluated through 12 months from randomization)
- Unplanned cardiovascular hospitalizations--secondary analysis using Anderson-Gill extension(Evaluated through 12 months from randomization)
- Win Ratio(Evaluated through 12 months from randomization)
- All-cause mortality(Evaluated through 12 months from randomization)