Early Dronedarone Versus Usual Care to Improve Outcomes in Persons With Newly Diagnosed Atrial Fibrillation

Atrial Fibrillation Clinical Trial

— CHANGE-AFIB  

Official title:

Pragmatic Randomized Clinical Trial of Early Dronedarone Versus Usual Care to Change and Improve Outcomes in Persons With First-Detected Atrial Fibrillation

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT05130268
• Other study ID #: 176131-M
• Status: Active, not recruiting
• Phase: Phase 4
• Start date: October 29, 2021
• Est. completion date: December 2024

Study information

• Verified date: November 2023
• Source: American Heart Association
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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:

Dronedarone is approved by the Food and Drug Administration to reduce the risk of hospitalization for AF in patients with paroxysmal or persistent AF. The efficacy and safety of dronedarone 400 mg twice daily was evaluated in five controlled studies, ATHENA, ANDROMEDA, European Trial in Atrial Fibrillation or Flutter Patients Receiving Dronedarone for the Maintenance of Sinus Rhythm (EURIDIS), ADONIS, and Dronedarone Atrial FibrillatioN study after Electrical Cardioversion (DAFNE), involving more than 6,000 patients with including more than 3200 patients who received dronedarone. As with any therapeutic agent, there are known risks with dronedarone therapy. These risks include hepatic injury, heart failure exacerbation, increased exposure to digoxin, increased plasma concentration of tacrolimus, sirolimus, and other Cytochrome P450, family 3, subfamily A (CYP 3A) substrates, and very rare instances of pulmonary toxicity. The risks of dronedarone are felt to be outweighed by its benefits. The guideline recommendations provided by the European Society of Cardiology and American Heart Association (AHA)/American College of Cardiology (ACC)/Heart Rhythm Society (HRS) are commensurate with this risk benefit assessment.

Benefit Assessment:

While there are no completed randomized clinical trials to guide selection or initiation of rhythm control therapies in patients with first-detected AF, there are recent trials that suggest benefit with both dronedarone antiarrhythmic therapy and early-initiation of rhythm control in persons with AF. the recent EAST-AFNET 4 trial demonstrated that early introduction of a comprehensive rhythm-control strategy (within one year of diagnosis) is superior to usual guideline-recommended care in improving cardiovascular (CV) outcomes at 5 years. The median time from new-onset AF to randomization in the EAST-AFNET4 trial was 36 days. The trial found that early rhythm control reduced the primary outcome of CV death, stroke, hospitalization for HF, or acute coronary syndrome (HR 0.79, 95% confidence interval 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. Thus, the investigators hypothesize that early initiation of dronedarone in patients with new-onset AF will lead to a reduction in CV hospitalization or death.

Overall Design:

Dronedarone is approved by the Food and Drug Administration to reduce the risk of CV hospitalization in patients with AF or atrial flutter. However, it is unknown if dronedarone (or any antiarrhythmic medication) can reduce CV hospitalization or death in patients with first-detected AF. This trial has been designed to address this important question. In order to facilitate the trial enrollment, data collection, and a generalizability to clinical practice, the CHANGE AFIB study has been designed as an open-label pragmatic clinical trial nested within the Get With The Guidelines (GWTG) Atrial Fibrillation registry. At present the overall GWTG program is being implemented in over 2,300 hospitals across the U.S. and is comprised of over 9 million patient records, with an estimated 650,000 new patient records entered per year. The trial will utilize the existing GWTG registry network, data collection architecture, and experience to facilitate both enrollment and conduct of the trial.

The comparator arm will be "usual care." Thus, this study will compare usual care plus dronedarone versus usual care alone. 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 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.

CHANGE AFIB will leverage several critical advantages as a pragmatic clinical trial. Data collection will be integrated into the Get With The Guidelines AFIB registry. The use of the GWTG-AFIB registry will also enhance subject recruitment and ensure the enrollment of a diverse group of patients. The randomized intervention will be compared with usual care thus further enhancing generalizability. Follow-up visits will be minimized to reduce patient burden. Moreover, follow-up visits will have "windows" to accommodate variation in follow-up intervals at different centers.

Justification for Study Drug Intervention and Dose:

Dronedarone is a non-iodinated benzofuran similar to amiodarone but is not associated with thyroid or pulmonary toxicity in randomized clinical trials or post-marketing observational studies. Dronedarone has electrophysiological characteristics spanning all 4 Vaughan-Williams anti-arrhythmic classes, with primarily class III effects. Initial trials suggested that dronedarone prolonged the time to recurrence of AF and reduced cardiovascular death and hospitalization.

The landmark ATHENA trial evaluated the efficacy and safety of dronedarone in patients with atrial arrhythmias (atrial fibrillation or atrial flutter). This trial did not include patients with a recent history of New York Heart Association (NYHA) class IV heart failure or recent hospitalization for decompensated heart failure (<4 weeks). Approximately, 30% of the ATHENA population had NYHA class I-III heart failure. ATHENA demonstrated that dronedarone 400 mg twice daily (in combination with background therapy) reduced the combined endpoint of CV hospitalization or death from any cause by 24% (p<0.001) compared with placebo. Of course, the ATHENA trial was not conducted in the special population of patients with a new diagnosis of AF. There are no randomized trials or guideline recommendations for antiarrhythmic therapy at the time of first-detected AF. A subgroup analysis from the ATHENA trial suggests that optimal outcomes may be achieved in those patients with shorter duration of AF (time from diagnosis). Similar observations have also been made in patients undergoing other forms of rhythm control, including catheter ablation. In this trial, patients with first-detected AF will be randomized to dronedarone on top of usual care versus usual care alone. Patients randomized to the intervention arm will be prescribed and treated with Dronedarone 400 mg bid. This dose has been chosen as it is the Food and Drug Administration approved dose as well as the dose recommended in current international guidelines. Dronedarone has also been shown to be an effective rate control agent as well. In the ERATO study treatment with dronedarone 400 mg twice daily let to a mean reduction of 24.5 beat/min in patients with permanent AF when compared with placebo. In the EURIDIS/ADONIS studies the mean difference in patients with paroxysmal/persistent AF during AF recurrence was 14 beats/min. Moreover, the dronedarone treated patients experienced improved rate control without any reduction in exercise tolerance as measured by maximal exercise.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 3000
• Est. completion date: December 2024
• Est. primary completion date: June 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 21 Years and older

Eligibility

Inclusion Criteria:

1. Age >=21 years.

2. First-detected atrial fibrillation (defined as atrial fibrillation diagnosed in the previous 120 days).

3. Electrocardiographic documentation of atrial fibrillation.

4. Estimated life expectancy of at least 1 year.

5. 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.

Exclusion Criteria:

1. Patients with prior or planned treatment with rhythm control, either catheter ablation or chronic (>7 days) antiarrhythmic drug therapy.

3. Planned cardiothoracic surgery. 4. New York Heart Association class III or IV heart failure or a hospitalization for heart failure in the last 4 weeks.

5. Patients with reduced ejection fraction (LVEF =40%). 6. Permanent atrial fibrillation.

7. Ineligible for oral anticoagulation, unless CHA2DS2-VASc is less than 3 in women or 2 in men.

8. Bradycardia with a resting heart rate < 50 bpm 9. PR interval >280 msec or 2nd degree or 3rd degree atrioventricular block without a permanent pacemaker/cardiac implanted electronic device.

10. Corrected QT interval >=500 msec. 11. Pregnancy or breast feeding. 12. Severe hepatic impairment in the opinion of the investigator.

Related Conditions & MeSH terms

• Atrial Fibrillation

Intervention

Drug:
• Dronedarone
Dronedarone 400 mg twice daily in addition to usual care

Locations

Country	Name	City	State
United States	Albany Medical Center	Albany	New York
United States	Luminis Health Anne Arundel Medical Center	Annapolis	Maryland
United States	Ascension Seton Medical Center Austin	Austin	Texas
United States	Saint Agnes Hospital	Baltimore	Maryland
United States	McLaren Bay Region	Bay City	Michigan
United States	Brigham and Womens Hospital	Boston	Massachusetts
United States	NYC Health and Hospitals - Jacobi	Bronx	New York
United States	NYC Health and Hospitals - Lincoln	Bronx	New York
United States	NYC Health and Hospitals - North Central Bronx	Bronx	New York
United States	Cooper University Hospital	Camden	New Jersey
United States	Penn State Health Holy Spirit Medical Center	Camp Hill	Pennsylvania
United States	Mt Sinai Hospital Medical Center	Chicago	Illinois
United States	Rush University Medical Center	Chicago	Illinois
United States	University of Illinois Hospital	Chicago	Illinois
United States	The MetroHealth System	Cleveland	Ohio
United States	University Hospital - University of Missouri	Columbia	Missouri
United States	Kettering Health Dayton	Dayton	Ohio
United States	Miami Valley Hospital	Dayton	Ohio
United States	DMC Harper University Hospital (AKA Wayne State University Hospital)	Detroit	Michigan
United States	Duke University Hospital	Durham	North Carolina
United States	Durham VA Health Care System	Durham	North Carolina
United States	Thomas Hospital	Fairhope	Alabama
United States	Parkview Hospital, Inc.	Fort Wayne	Indiana
United States	Texas Health Fort Worth (FKA Texas Health Harris Methodist Hospital Fort Worth)	Fort Worth	Texas
United States	Northeast Georgia Medical Center	Gainesville	Georgia
United States	Mercy Gilbert Medical Center	Gilbert	Arizona
United States	Heart Clinic of Hammond	Hammond	Louisiana
United States	Penn State Health Milton S Hershey Medical Center	Hershey	Pennsylvania
United States	Memorial Hermann - Texas Medical Center	Houston	Texas
United States	Ascension St Vincent Hospital - Indianapolis	Indianapolis	Indiana
United States	First Coast Cardiovascular Institute	Jacksonville	Florida
United States	Riverside Medical Center	Kankakee	Illinois
United States	Kansas City Heart and Vascular Specialists at Providence Medical Center	Kansas City	Kansas
United States	Kettering Medical Center	Kettering	Ohio
United States	Mayo Clinic Hospital - Franciscan Healthcare La Crosse	La Crosse	Wisconsin
United States	Colorado Heart & Vascular Group - St. Anthony's Hospital	Lakewood	Colorado
United States	Sparrow Hospital	Lansing	Michigan
United States	Baptist Health Lexington	Lexington	Kentucky
United States	Saint Joseph Hospital	Lexington	Kentucky
United States	Cedars Sinai Medical Center	Los Angeles	California
United States	Los Angeles Medical Center (Kaiser Permenente)	Los Angeles	California
United States	West Los Angeles Medical Center	Los Angeles	California
United States	Georgia Arrhythmia Consultants and Research Institute	Macon	Georgia
United States	University Hospital - University of Wisconsin-Madison	Madison	Wisconsin
United States	UW Health at the American Center (AKA UW Health East Madison Hospital)	Madison	Wisconsin
United States	Wellstar Kennestone Hospital	Marietta	Georgia
United States	Marshfield Medical Center	Marshfield	Wisconsin
United States	McLaren - St Lukes Hospital	Maumee	Ohio
United States	Loyola University Medical Center	Maywood	Illinois
United States	Texas Institute of Cardiology	McKinney	Texas
United States	Enmanuel Advanced Research Center, LLC	Miami	Florida
United States	Excellence Medical And Research, LLC	Miami	Florida
United States	Golden Touch Clinical Research	Miami	Florida
United States	Life Spring Research Foundation, LLC	Miami	Florida
United States	Nouvelle Clinical Research LLC	Miami	Florida
United States	The Miami Research Group	Miami	Florida
United States	Ocean Wellness Center, LLC	Miami Gardens	Florida
United States	Pharma Medical Innovations	Miami Lakes	Florida
United States	The Angel Medical Research	Miami Lakes	Florida
United States	Minneapolis VA Health Care System	Minneapolis	Minnesota
United States	Trinity Hospital	Minot	North Dakota
United States	Synapse Clinical Research	Missouri City	Texas
United States	JW Ruby Memorial Hospital	Morgantown	West Virginia
United States	McLaren Macomb	Mount Clemens	Michigan
United States	Ascension Saint Thomas Midtown	Nashville	Tennessee
United States	Tulane Medical Center	New Orleans	Louisiana
United States	Memorial Sloan Kettering	New York	New York
United States	NewYork-Presbyterian/Columbia University Irving Medical Center	New York	New York
United States	Christiana Hospital	Newark	Delaware
United States	Captain James A Lovell Federal Health Care Center	North Chicago	Illinois
United States	DiGiovanna Institute for Medical Education & Research	North Massapequa	New York
United States	Oklahoma City VA Health Care System	Oklahoma City	Oklahoma
United States	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma
United States	CHI Health Creighton University Medical Center - Bergan Mercy	Omaha	Nebraska
United States	UC Irvine Medical Center (AKA UCI Health)	Orange	California
United States	Overland Park Regional Medical Center	Overland Park	Kansas
United States	Methodist Medical Center of Illinois	Peoria	Illinois
United States	Proctor Community Hospital	Peoria	Illinois
United States	WakeMed Raleigh Campus	Raleigh	North Carolina
United States	Penn State Health St Joseph Medical Center - Main Campus	Reading	Pennsylvania
United States	Chippenham and Johnston Willis Medical Center	Richmond	Virginia
United States	Hunter Holmes McGuire VA Medical Center (AKA Richmond VA Medical Center)	Richmond	Virginia
United States	The Valley Hospital	Ridgewood	New Jersey
United States	Trinity Rock Island	Rock Island	Illinois
United States	Adventist Healthcare Shady Grove Medical Center	Rockville	Maryland
United States	Barnes-Jewish Hospital (AKA Washington Univ)	Saint Louis	Missouri
United States	SSM Health Saint Louis University Hospital	Saint Louis	Missouri
United States	Northside Hospital	Saint Petersburg	Florida
United States	University of Utah Hospital	Salt Lake City	Utah
United States	University Hospital at University of Texas San Antonio	San Antonio	Texas
United States	HonorHealth Scottsdale Shea Medical Center	Scottsdale	Arizona
United States	Mercy Hospital Springfield	Springfield	Missouri
United States	St. Elizabeth's Hospital of the Hospital Sisters of the Third Order of St. Francis	Springfield	Illinois
United States	St. John's Hospital of the Hospital Sisters of the Third Order of St. Francis	Springfield	Illinois
United States	Guardian Angel Research Center	Tampa	Florida
United States	Los Robles Health System - Los Robles Regional Medical Center	Thousand Oaks	California
United States	UCLA Medical Center - Harbor	Torrance	California
United States	Carle Foundation Hospital	Urbana	Illinois
United States	Colorado Heart & Vascular Group - St. Anthony's North Health Campus	Westminster	Colorado
United States	Marshfield Medical Center	Weston	Wisconsin
United States	New Hanover Regional Medical Center	Wilmington	North Carolina
United States	Wooster Community Hospital Health System	Wooster	Ohio
United States	Trinity Health Ann Arbor Hospital - Michigan Heart	Ypsilanti	Michigan

Sponsors (3)

Lead Sponsor	Collaborator
American Heart Association	Duke Clinical Research Institute, Sanofi

Country where clinical trial is conducted

United States, 

References & Publications (66)

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* Note: There are 66 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Any unplanned arrhythmia-related hospitalization	Arrhythmia-Related Hospitalization will be defined as any unplanned hospitalization (i.e. admission with an overnight stay in an acute care healthcare facility/hospital) due to any tachy or brady-arrhythmia.	Evaluated through 12 months from randomization
Other	Number of participants who experience AF progression	AF Progression will be defined as the transition from (a) paroxysmal to persistent or (b) persistent to permanent AF.	Evaluated through 12 months from randomization
Other	Number of participants who undergo cardioversion (pharmacologic or electrical)	Cardioversion (either pharmacologic or electrical) with or without transesophageal echocardiographic guidance will be a tertiary endpoint.	Evaluated through 12 months from randomization
Other	Number of participants who have ablation of AF (catheter, surgical or hybrid) performed	Ablation of AF including catheter ablation, surgical ablation, or hybrid (endocardial and epicardial ablation) ablation will be a tertiary endpoint.	Evaluated through 12 months from randomization
Other	Days alive and outside of the hospital	Days Alive and Out of the Hospital. Days alive and out of the hospital (DAOH, also referred to as "home time") is an emerging clinical trial endpoint that is both pragmatic and patient centered. It is highly correlated with traditional time-to-event mortality and hospitalization outcomes.	Evaluated through 12 months from randomization
Other	Patient-Reported Quality of Life--AFEQT	The AFEQT is a 21-item, AF-specific health-related QOL questionnaire that assesses the impact of AF on patient-reported quality of life. The AFEQT includes a summary score (calculated from 18 of the questions) and subscale scores in three domains: symptoms, daily activities, and treatment concern. The summary and subscale scores range from 0 (corresponds to complete AF-related disability) to 100 (no AF-related disability). A change of 5 or more points in the AFEQT has been identified as a benchmark for a clinically meaningful difference in an individual patient.	At baseline and 12 months
Other	Patient-Reported Quality of Life--MAFSI	The MAFSI was developed as a modification and update of the AF Symptom Checklist. The trial will use a modified MAFSI questionnaire comprised of a 10-item AF symptom checklist that asks about frequency and severity of each symptom. Frequency of symptoms is recorded as 0 (never), 1 (rarely), 2 (sometimes), 3 (often), or 4 (always). These responses are summed for a total Frequency Score that ranges from 0 (no AF symptoms) to 40 (worst score). MAFSI Severity Scores are recorded as 1 (mild), 2 (moderate), or 3 (extreme). Severity scores are summed and range from 0 (no AF symptoms) to 30 (most severe AF symptoms). A clinically meaningful change in the MAFSI has not previously been established and therefore will be considered to be about ¼ of the pooled baseline standard deviation (SD), or 1.6 points for the Frequency Score and 1.3 points for the Severity Score.	At baseline and 12 months
Primary	Cardiovascular Hospitalization or Death	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.	Evaluated through 12 months from randomization
Secondary	Win Ratio	Among the randomized patients, every patient in the dronedarone arm will be compared with every patient in the usual care arm. Within each pair of patients, the component outcomes will be compared in descending order of importance until one of the patients in the pair demonstrates a better outcome compared with the other. For the purpose of this trial the hierarchy of component outcomes are shown below. The components in the WIN ratio hierarchy are similar to the endpoints considered in the recent EAST AFNET4 trial.; Hierarchy of Outcomes for the WIN Ratio: All-cause mortality; Ischemic stroke or systemic embolism; Hospitalization for new/worsening diagnosis of heart failure; Hospitalization for acute coronary syndrome	Evaluated through 12 months from randomization
Secondary	All-cause mortality	For descriptive purposes, deaths will be categorized by the site investigators according to the following categories: cardiovascular and non-cardiovascular. Cardiovascular deaths will be further classified into arrhythmic vs non-arrhythmic according the modified Hinkle-Thaler criteria, as used in several landmark cardiovascular trials. Patients who are well and (1) have a witnessed sudden collapse or (2) those found dead, but known to be alive and well in the previous 24 hours (e.g. no signs or symptoms of cardiorespiratory distress) will be defined as having arrhythmic death.	Evaluated through 12 months from randomization
Secondary	Ischemic stroke or systemic embolism	The occurrence of ischemic stroke will be defined as an acute episode of focal or global neurological dysfunction caused by brain, spinal cord, or retinal vascular injury as a result of hemorrhage or infarction. Symptoms or signs must persist =24 hours, unless the stroke is documented by CT, MRI or autopsy, in which case the duration of symptoms/signs may be less than 24 hours. Stroke may be classified as ischemic (including hemorrhagic transformation of ischemic stroke), hemorrhagic, or undetermined. Systemic embolism will be defined as acute arterial insufficiency or occlusion of the extremities or any non-CNS organ associated with clinical, imaging, surgical/autopsy evidence of arterial occlusion in the absence of other likely mechanism (e.g., trauma, atherosclerosis, or instrumentation).	Evaluated through 12 months from randomization
Secondary	Hospitalization for new/worsening diagnosis of heart failure	Hospitalization for new or worsening heart failure will be defined as any unplanned hospitalization (i.e. admission with an overnight stay in an acute care healthcare facility/hospital) due to a new diagnosis or worsening symptomatic heart failure	Evaluated through 12 months from randomization
Secondary	Hospitalization for acute coronary syndrome	Any hospitalization (i.e. admission with an overnight stay in an acute care healthcare facility/hospital) due to acute coronary syndrome.	Evaluated through 12 months from randomization
Secondary	Time to first unplanned cardiovascular hospitalization	Given the importance of CV hospitalization as an outcome from a clinical perspective, patient perspective, and economic perspective, there will be two analyses of CV hospitalization. The key secondary endpoint will be time to first unplanned CV hospitalization (similar to the component of the primary endpoint).	Evaluated through 12 months from randomization
Secondary	Unplanned cardiovascular hospitalizations--secondary analysis using Anderson-Gill extension	Given the importance of CV hospitalization as an outcome from a clinical perspective, patient perspective, and economic perspective, there will be two analyses of CV hospitalization. The second exploratory analysis of unplanned cardiovascular hospitalization will use a method to account for repeated events (Anderson-Gill extension).	Evaluated through 12 months from randomization