A Randomized Controlled Trial to Assess Abstinence of Coffee Compared to Continued Consumption on Recurrent Atrial Fibrillation Following Cardioversion
Phase: NA
Conditions: Atrial Fibrillation, Coffee
Sponsor: University of California, San Francisco

 
 
 
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DECAF 
 
Does Eliminating Coffee Avoid Fibrillation? 
 
A randomized controlled trial to assess abstinence of coffee compared to continued 
consumption on recurrent atrial fibrillation following cardioversion  
 
 
Author(s): 
Gregory M. Marcus, MD, MAS 
Principal Investigator, University of California, San Francisco 
 
Christopher X. Wong, MBBS, PhD 
Cardiac Electrophysiologist, The University of Adelaide 
 
Document type: 
Protocol  
Version: 
1.4 
Release date: 
June 12, 2025 
Center: 
University of California, San Francisco 
505 Parnassus Ave, San Francisco, CA  94143, USA 
Funder: 
None 
 
 
 
 
 
 
 
 
 
 

 
 
 
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Authored by the following: 
 
 
Gregory M. Marcus, MD, MAS  
(Principal Investigator) 
 
signature  
 
date 
 
 
Christopher X. Wong, MBBS, PhD  
(Cardiac Electrophysiologist) 
 
signature  
 
date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
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TABLE OF CONTENTS 
ADMINISTRATIVE INFORMATION SUMMARY ....................................................................................................... 5 
1.0  INTRODUCTION ............................................................................................................................................. 6 
1.1.  BACKGROUND AND SIGNIFICANCE ............................................................................................................................. 6 
1.2.  POSSIBLE MECHANISMS OF COFFEE AND ITS CONSTITUENTS ........................................................................................... 6 
1.3.  PRIOR OBSERVATIONAL STUDIES ON COFFEE, CAFFEINE, AND AF .................................................................................... 6 
1.4.  CURRENT CONSUMER AND PHYSICIAN BELIEFS ............................................................................................................. 7 
1.4.  RATIONALE FOR CURRENT STUDY .............................................................................................................................. 7 
2.0  INVESTIGATIONAL PLAN ................................................................................................................................ 8 
2.1  
STUDY DESIGN .................................................................................................................................................. 8 
2.1.1 
Study Visits and Windows ..................................................................................................................... 8 
2.2   
STUDY OBJECTIVES ............................................................................................................................................. 9 
2.3   
INCLUSION/EXCLUSION CRITERIA ........................................................................................................................ 10 
2.3.1   
Inclusion Criteria ................................................................................................................................. 10 
2.3.2  
Exclusion Criteria ................................................................................................................................ 10 
4.1 
RANDOMIZED PARTICIPANTS – WITH EXCLUSION FOUND ON DAY OF CARDIOVERSION .................................................... 11 
4.2  
UNSUCCESSFUL CARDIOVERSION ......................................................................................................................... 11 
4.3  
PARTICIPANT WITHDRAWALS ............................................................................................................................. 11 
4.4  
OTHER EARLY TERMINATIONS ............................................................................................................................ 11 
5.0   STUDY PROCEDURES ................................................................................................................................... 12 
5.1   
SCREENING FOR INCLUSION/EXCLUSION CRITERIA .................................................................................................. 13 
5.5 
ELECTROCARDIOGRAM (ECG) ............................................................................................................................ 13 
5.6 
PHYSICAL EXAMINATION AND MEDICAL HISTORY ................................................................................................... 13 
5.7  
TARGETED MEDICATION INVENTORY ................................................................................................................... 13 
6.0 RISKS AND BENEFITS OF THE STUDY ............................................................................................................. 13 
6.1   
CARDIOVERSION PROCEDURE ............................................................................................................................. 14 
6.2   
COFFEE ABSTINENCE OR CONTINUATION .............................................................................................................. 14 
7.0  STUDY ROLES ............................................................................................................................................... 14 
7.1   
ADMINISTRATIVE ORGANIZATION ........................................................................................................................ 14 
7.2.1   
CLINICAL SITE PRINCIPAL INVESTIGATOR ........................................................................................................... 14 
9.0 QUALITY ASSURANCE AND DATA MANAGEMENT ......................................................................................... 15 
9.1 
CLINICAL SITE INVESTIGATOR AND COORDINATOR TRAINING .................................................................................... 15 
9.2 
DATA HANDLING AND CONFIDENTIALITY .............................................................................................................. 15 
9.3  
SOURCE DOCUMENTS ....................................................................................................................................... 15 
9.4  
DATA COLLECTION AND MANAGEMENT ............................................................................................................... 15 
9.5  
DATA MONITORING ......................................................................................................................................... 16 
10.0 STATISTICAL METHODS .............................................................................................................................. 16 
10.1  
SAMPLE SIZE AND RANDOMIZATION ................................................................................................................ 16 
10.2  
INTENTION-TO-TREAT (ITT) ........................................................................................................................... 16 
11.0  PUBLICATION ............................................................................................................................................ 16 
12.0 ETHICAL CONSIDERATIONS ......................................................................................................................... 17 
12.1  
INSTITUTIONAL REVIEW BOARD (IRB) AND ETHICS COMMITTEE (EC) APPROVAL ..................................................... 17 
12.2  
INFORMED CONSENT .................................................................................................................................... 17 
12.3  
DECLARATION OF HELSINKI ............................................................................................................................ 17 

 
 
 
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SUMMARY OF PROTOCOL CHANGES .................................................................................................................. 18 
BIBLIOGRAPHY ................................................................................................................................................... 20 
 
 
 
 
 
 
 
 
 
 

 
 
 
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ADMINISTRATIVE INFORMATION SUMMARY 
 
 Project Title: 
Does Eliminating Coffee Avoid Fibrillation (DECAF) 
 
 
Coordinating Center   
Principal Investigator: 
 
Gregory M. Marcus, MD, MAS, FACC, FAHA, FHRS 
 
 
Mailing Address: 
University of California, San Francisco 
505 Parnassus Avenue, M-1180B 
San Francisco, CA  94143-0124 
USA 
 
 
Telephone: 
1 (415) 476-3450 
 
 
E-Mail: 
greg.marcus@ucsf.edu 
 
 
Emergency Contact: 
On-Call Electrophysiology Fellow 
University of California, San Francisco 
505 Parnassus Avenue, M-1180B 
San Francisco, CA  94143-0124 
USA 
 
Telephone: 
1 (415) 476 1000 
 

 
 
 
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1.0  INTRODUCTION  
 
1.1.  Background and Significance 
 
Atrial fibrillation (AF) is the most common, sustained heart rhythm disorder experienced by humans. It is 
anticipated that more than 10 million individuals in the United States will have AF by 2050.[1] This is concerning as 
AF is associated not only with complications including heart failure, stroke, and premature death, but also 
troubling symptoms such as palpitations, dyspnea, and fatigue.[2] As a result, the burden of AF-related symptoms 
and complications on affected individuals and society is growing, as represented by increasing hospitalizations and 
healthcare costs.[3] There is thus a pressing need to characterize modifiable factors that may reduce the incidence, 
prevalence, and overall impact of AF. 
 
Coffee is one of the most ubiquitously consumed substances worldwide. In addition to caffeine, coffee contains a 
variety of other biologically active compounds.[4] Correspondingly, whether any effect of coffee on health 
outcomes exists is of considerable interest to physicians, scientists, and individual consumers. While significant 
data exist on the potential impact of coffee on many cardiometabolic parameters, [4] there is conflicting data on 
any role of coffee on AF.[5] Given both the increasing population impact of AF and the widespread use of coffee in 
society, determining even a modest associated benefit or risk would be of great clinical relevance.  
 
1.2.  Possible Mechanisms of Coffee and its Constituents 
 
Amongst the constituent compounds in coffee, the majority of prior research has focused on caffeine. While the 
caffeine content of coffee varies significantly, an average cup is estimated to contain between 95 and 200mg of 
caffeine.[6] Caffeine is a methylxanthine alkaloid and a potent central nervous system stimulant. It also exerts a 
range of cardiovascular effects that may facilitate atrial arrhythmogenesis. This includes sympathetic stimulation, 
enhanced automaticity, and increased after depolarization-induced triggered activity.[5] Conversely, caffeine also 
has mechanisms that might reduce AF; for example, caffeine inhibits adenosine which can trigger AF, and it 
additionally has some antioxidant activity. Finally, it has been estimated that coffee contains over 1,000 
compounds, including some with described biological effects such as diterpene alcohols and chlorogenic acid.[4] As 
a result, there are plausible mechanisms for coffee and its constituents to have both beneficial and harmful 
cardiovascular and arrhythmic effects.  
 
1.3.  Prior Observational Studies on Coffee, Caffeine, and AF 
 
A number of prior observational studies have evaluated the role of chronic coffee consumption and incident AF 
with varied results. In the Multifactor Primary Prevention Study, moderate coffee consumption of 1-4 cups per day 
was associated with increased risk.[7] Similarly, intermittent coffee consumption of less than 0.5 cups/day 
appeared to be associated with greater AF risk in the Multi-Ethnic Study of Atherosclerosis.[8] In contrast, several 
reports have found no clear relationship between coffee or caffeine intake and incident AF. These include reports 
from the Danish Diet, Cancer, and Health Study,[9] the Framingham heart Study,[10] two Cohort of Swedish 
Men,[11] and the Swedish Mammography Cohort.[11] Conversely, other studies have described results potentially 
consistent with a linear benefit of increasing coffee consumption. These include reductions of risk in hospitalized 
Kaiser Permanente patients,[12] an updated analysis from the Danish Diet, Cancer, and Health Study,[13] an Italian 
cohort,[14] and the UK Biobank.[15]  Finally, a few investigators have demonstrated J- or U-shaped associations 
with benefit at modest intakes no effect or harm at higher levels, such as that seen in the Women’s Health 
Study,[16] Physicians’ Health Study,[17] the Seguimiento Universidad de Navarra (SUN) cohort,[18] and the 
Prevencion con Dieta Mediterranea (PREDIMED) cohort.[18] Meta-analyses including the aforementioned studies 
have concluded either no effect or a reduced AF risk with coffee consumption.[11, 19, 20]  Furthermore, 
Mendelian randomization techniques using alleles associated with caffeine metabolism and hence coffee 
consumption have also not provided supportive evidence for any significant effect on AF.[15, 21]   
 
Comparatively fewer studies exist on the role of acute coffee or caffeine ingestion, or on AF and related outcomes 
in other settings. One study found that acute intravenous administration of caffeine did not alter invasive 
measures of cardiac conduction or refractoriness.[22] Two reports suggest that modest coffee consumption may 

 
 
 
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be associated with a greater likelihood for spontaneous cardioversion compared to higher consumption.[23, 24] 
Furthermore, no association between caffeine intake and atrial ectopy was found in another analysis from the 
Cardiovascular Health Study.[25]  
 
1.4.  Current Consumer and Physician Beliefs 
 
Despite the varied evidence described above, established notions exist that coffee and caffeine contribute to AF 
and/or trigger AF episodes. In a large study of symptomatic patients with paroxysmal AF, caffeine was reported as 
the second most common triggering factor in almost one-third of individuals.[26]  Prior surveys of physicians have 
also suggested reductions in caffeine to assist with arrhythmias.[27] Conversely, professional society guidelines 
either do not discuss coffee or caffeine [28] or suggest they are unlikely to contribute based on recent studies.[29]  
 
1.4.  Rationale for Current Study 
 
A key limitation of existing data on the effects of coffee and caffeine on AF has been their observational nature. 
Even with careful study design methodology, including prospective data collection, comprehensive 
characterization of participants, and appropriate analytical techniques, it is challenging if at all feasible to eliminate 
the possibility of biases in observational studies such as residual confounding and reverse causality.[30] Instead, 
appropriate randomization of subjects to an exposure of interest is more likely to produce reliable, unbiased 
results where observational evidence is conflicting or requires confirmation.[31] To the best of our knowledge, no 
such assessment on the effect of coffee on AF outcomes has been undertaken to date.  
 
While the general effect of coffee or caffeine on incident AF would be of significant interest, undertaking a 
randomized trial in this setting would be challenging and likely to require an extremely large number of otherwise 
healthy individuals to agree to consume or abstain. Many individuals may find this objectionable given the widely 
consumed nature of coffee and caffeine-containing substances.  
 
An alternative and potentially more practical setting would be in patients with existing AF who are not only at 
higher risk for (recurrent) AF episodes but may be more likely to be interested in such a randomized evaluation 
given their personal situation.  
 
Thus, this study proposes to evaluate the effect of random allocation to coffee abstinence compared to continued 
caffeinated coffee consumption in patients undergoing cardioversion for AF, with patients being followed up for 
recurrent episodes of AF.  
 
This study will provide the first, randomized evaluation of coffee on AF outcomes. Given the conflicting evidence to 
date and widespread consumption of coffee, this study will be of significant interest to consumers and physicians 
alike.  
 
 

 
 
 
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2.0  INVESTIGATIONAL PLAN 
 
2.1  
Study Design 
 
This study is an investigator-initiated, prospective, open-label, randomized (1:1) clinical trial of coffee abstinence 
compared to coffee continuation on recurrent AF  in patients undergoing cardioversion. 
 
This study will be conducted at the coordinating center in the United States (the University of California, San 
Francisco), in Australia (University of Adelaide), and in Canada (Sunnybrook Health Sciences Centre).  Two-hundred 
(200) participants total will be enrolled and randomized. 
 
2.1.1 
Study Visits and Windows 
 
After screening and eligibility has been determined, participants will be enrolled and randomized at the baseline 
visit (date of cardioversion).  
 
No in-person follow-up visits will be required. Phone call follow-ups will be conducted at week 1, month 1, month 
3, and month 6 until first recurrence of AF or study completion (whichever comes first).  This will be supplemented 
with chart review, including scanned medical records if the patient does not return for medical care, and analyses 
of ECG strips obtained from AliveCor (San Francisco, CA) KardiaMobile devices and Apple Watch (Cupertino, CA) 
devices already owned and in use by patients.  
 
Table 1 outlines the window for each of the study visits.  Clinical sites should make every possible effort to ensure 
that each study visit is conducted within the specified window. 
 
Table 1.  Visit Windows 
Study Visit 
Scheduled Timepoint 
Visit Window  
V1a-V1b (Screening) 
 
 
V1c (Baseline) 
Enrollment/Cardioversion 
 
V2 
Month 1* 
+/- 7 days 
V3 
Month 3* 
+/- 7 days 
V4 
Month 6* 
+/- 14 days 
*Follow-up visits will be calculated from the date of cardioversion (i.e., baseline).     
 
 
In the occasional event that routine clinical pre-operative care does not allow adequate time for study 
coordinators to approach potentially eligible patients for the baseline visit prior to their cardioversion procedure, 
study coordinators may call patients who were successfully cardioverted to normal sinus rhythm within a week 
after their cardioversion procedure to see if they are interested in participating. Visits V1a-V1c will be carried out 
remotely in this case. In this occasional remote situation, if a patient chooses to take part in the study, informed 
consent will be obtained through Docusign and they will be randomized to either continue or abstain from 
coffee. Phone call follow-ups Visits V2-V4 will accordingly be conducted at month 1, month 3, and month 6 until 
first recurrence of AF or study completion (whichever comes first).

 
 
 
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Figure 1.  Study Flow Diagram 
 
 
 
 
 
 
 
 
 
 
 
Baseline Visit (Cardioversion) 
 
§ 
Enrollment 
§ 
Demographics 
§ 
Height and weight 
§ 
Detailed history of coffee consumption habits 
§ 
Detailed history of alcohol consumption habits 
§ 
Detailed medical and medication history 
§ 
Cardioversion 
§ 
Assess pre- and post-cardioversion ECG 
§ 
Randomization to allocated treatment (coffee abstinence or continuation), provided as an instruction 
card and/or instruction letter they receive after cardioversion  
 
Follow-Up Phone Calls at Month 1, 3, and 6 
 
§ 
Compliance with allocated treatment 
§ 
Consumption of coffee or other caffeinated products, if applicable 
§ 
Consumption of alcohol 
§ 
Symptomatic and/or known diagnosis of recurrent AF  
§ 
ECG strips from patient owned AliveCor KardiaMobile or Apple Watch (if required) 
§ 
AE/SAE evaluation 
§ 
Vital status 
Pre-Cardioversion Screening 
 
§ 
Initial inclusion/exclusion evaluation 
§ 
Screen for coffee consumption habits (≥ 1 cup of coffee per day) 
§ 
Screen for significant other caffeinated product consumption 
§ 
Informed consent 
Recurrent AF Documentation from Physician/Healthcare Provider  
 
§ 
Documentation of ECG or any ambulatory ECG monitoring to confirm recurrent AF obtained from 
physician/healthcare provider if: 
o 
If patient reports diagnosis of recurrent AF 
o 
Patient not sure if has been diagnosed with recurrent AF 
o 
Patient declines further phone follow-up but still consents to access to physician/healthcare 
provider documentation 
o 
Patient unable to be contacted via phone 

 
 
 
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2.2   
Study Objectives 
 
The objectives of this clinical trial are to assess the effect of abstaining from coffee compared to continuation of 
coffee on the first recurrence of AF following cardioversion.  
 
Primary objectives:  
• 
To assess the number of people with first confirmed clinical recurrence of AF or atrial flutter, or device-
detected recurrence lasting longer than 30 seconds, following cardioversion in the coffee abstinence group 
compared to the continued caffeinated coffee consumption group analyzed as a time-to-event outcome 
 
Secondary exploratory objectives include assessment of the following: 
• 
Adverse events before censorship, including myocardial infarction, stroke or transient ischaemic attack, heart 
failure exacerbation, syncope, emergency department visit, hospitalization, and death 
• 
Atrial flutter and atrial fibrillation separately as incident outcomes 
 
2.3   
Inclusion/Exclusion Criteria 
 
2.3.1   
Inclusion Criteria 
 
Patients must meet all of the following to be eligible: 
1. Men or women ≥ 21 years of age 
2. Sustained atrial fibrillation or atrial flutter (provided patient has history of atrial fibrillation) 
3. Planned/scheduled direct current electrical cardioversion 
4. Consumption greater than or equal to one cup of coffee per day sometime in the past 5 years  
5. Willing and able to comply with coffee abstinence or continuation for at least 6 months 
6. Life expectancy of at least 6 months 
7. Willing and able to return and comply with scheduled phone follow up visits 
8. Willing and able to provide written informed consent 
 
2.3.2  
Exclusion Criteria 
Patients will be excluded if they meet any of the following: 
1. Established allergy or adverse reaction to coffee  
2. Stated inability to comply with coffee abstinence or continuation 
3. Atrial fibrillation ablation in preceding 3 months or planned in next 3 months 
4. Recent cardiothoracic surgery in preceding 3 months 
5. Pregnancy or desire to get pregnant within next 6 months. 
6. Current enrollment in an investigation or study of a cardiovascular device or investigational drug that would 
interfere with this study 
7. Any other criteria, which would make the patient unsuitable to participate in this study as determined by the 
Principal Investigator (e.g., an uncontrolled drug and/or alcohol addiction) 
 
3.0  STUDY TREATMENT 
 
After eligibility for the study has been confirmed, participants will be randomized to abstinence from coffee or 
continued consumption of caffeinated coffee. Participants will undergo this intervention until the primary 
endpoint of AF recurrence, end of study (month 6), or study withdrawal, after which they will consume or abstain 
from coffee at their discretion.  
 
3.1 
Coffee Abstinence  
 
If allocated to coffee abstinence, patients will be encouraged to completely abstain from coffee and other caffeine-
containing products as much as feasibly possible. As some decaffeinated coffee can also contain caffeine, patients 
will be encouraged to abstain from decaffeinated coffee as well. Other non-coffee caffeine-containing products to 

 
 
 
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avoid will include, but not be limited to, tea, cola, energy drinks, chocolate, chewing gum, and chocolate- or 
coffee-flavored foods (e.g. ice cream).  
 
 
3.2  
Continued Coffee Consumption 
 
If allocated to continued coffee consumption, patients will be encouraged to drink at least one cup of caffeinated 
coffee (or one espresso shot) daily and other caffeine-containing products as per their usual lifestyle. It will be 
recommended that patients do not intentionally increase or decrease consumption of these products.  
 
4.0 EARLY TERMINATION  
 
If a randomized participant terminates participation in the study early (i.e., prior to completion of all follow-up), 
the Principal Investigator will determine the primary reason for early termination and report this.  Participants who 
early terminate from the study will not be replaced with newly enrolled participants.   
 
4.1 
Randomized Participants – with exclusion found on day of cardioversion 
 
A proportion of patients scheduled for electrical cardioversion do not convert to sinus rhythm, outlined in more 
detail below. Thus, randomization will be undertaken after successful cardioversion from AF to sinus rhythm in 
order to minimize exclusion of randomized patients for this reason. 
 
In the event that another exclusion criterion is identified on the day of cardioversion after randomization has 
occurred, the participant may or may not continue to be treated as allocated as deemed appropriate by the 
Principal Investigator. All randomized patients will be included in the ITT analyses.  
 
4.2  
Unsuccessful cardioversion 
 
Patients will be interviewed and consented prior to cardioversion occurring. However, a small proportion of 
patients do not have successful cardioversion. As a result, randomization will occur after successful cardioversion 
from AF to sinus rhythm. Patients will be excluded in the event that cardioversion is unsuccessful.  
 
4.3  
Participant Withdrawals 
 
Each participant will be informed that participation in the study is voluntary and that he/she may withdraw from 
the study at any time without effect on subsequent medical treatment or relationship with the treating physician.  
Participants who discontinue follow-up at any time after randomization will be included in the ITT analyses. 
 
4.4  
Other Early Terminations 
 
Participants who discontinue follow-up at any time after randomization will be included in the ITT analyses. 
 
Lost to Follow-Up:  If a participant is unable to be contacted via phone for follow-up (i.e. participants who become 
lost to follow up and whose status is unclear because they fail to appear for study visits without stating an 
intention to withdraw) for any other reason and the study team is unable to confirm the status of their atrial 
fibrillation post-cardioversion upon review of their medical record at study follow up visits, the participant will be 
designated an early termination.  The clinical site Principal Investigator should show "due diligence" by 
documenting in the source documents, all steps taken to contact the participant, e.g., dates of telephone calls, 
registered letters, etc.   
 
In the absence of a stated intention to withdraw, the physician or other healthcare professional of participants 
may be contacted in an attempt to ascertain the presence or absence of AF recurrence.  
 

 
 
 
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Principal Investigator Determination:  Participants should also be early terminated at any time if the Principal 
Investigator concludes that it would be in the participant’s best interest for any reason.  Protocol deviations should 
not lead to early termination unless they indicate a significant risk to the participant’s safety.   
 
Early Study Closure:  The study may be terminated due to safety concerns.  Should this be necessary, participants 
currently in follow-up will be early terminated and scheduled for a Close-Out Visit, as soon as possible.   The 
Principal Investigator will be responsible for informing the appropriate local Institutional Review Board of the early 
study termination. 
 
5.0   STUDY PROCEDURES 
 
Table 2 provides an overview of the evaluations to be performed at each study visit/follow-up.  See also Figure 1, 
the study flow diagram, for details on timing of these evaluations.    
 
Table 2.   Schedule of Evaluations and Visits  
 
 
Screening 
Baseline 
Follow-Up Phone Calls 
 
Visits 1a-1b 
Visit 1c 
Visit 2 
Visit 3 
Visit 4 
 
 
 
Month 1 
Month 3 
Month 6 
 
 
Cardioversion 
 
 
 
Initial inclusion/exclusion 
evaluation 
X 
 
 
 
 
Screen for coffee consumption 
habits 
X 
 
 
 
 
Screen for significant other 
caffeinated product 
consumption 
X 
 
 
 
 
Informed consent 
X 
 
 
 
 
Demographics 
 
X 
 
 
 
Height and weight 
 
X 
 
 
 
Detailed history of coffee 
consumption habits 
 
X 
X 
X 
X 
Detailed history of alcohol 
consumption habits 
 
X 
X 
X 
X 
Detailed medical history 
 
X 
X 
X 
X 
Targeted medication history 
 
X 
X 
X 
X 
Assessment of clinically 
available pre-cardioversion 
ECG 
 
X 
 
 
 
Assessment of clinically 
available post-cardioversion 
ECG 
 
X 
 
 
 
Randomization 
 
X 
 
 
 
Detailed history of other 
caffeinated product 
consumption 
 
 
X 
X 
X 
AF symptoms  
 
 
X 
X 
X 
Assessment of AliveCor 
KardiaMobile or Apple Watch 
ECG strip  
 
 
X 
X 
X 
Assessment of clinically 
available ECG or ambulatory 
 
 
X 
X 
X 

 
 
 
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ECG monitoring from 
physician/healthcare provider  
Adverse events/serious 
adverse events evaluation 
 
 
X 
X 
X 
Targeted medical care 
utilization 
 
 
X 
X 
X 
Vital status 
 
 
X 
X 
X 
 
 
 
5.1   
Screening for Inclusion/Exclusion Criteria 
 
Each potential participant’s medical record will be briefly reviewed for available inclusion and exclusion criteria 
data. Potentially eligible patients will be subsequently approached to ascertain interest and coffee/other 
caffeinated product consumption.  After informed consent is obtained, pre- and post-cardioversion ECGs will be 
assessed to record AF and sinus (or other appropriate non-AF underlying) rhythm respectively. Once this is 
confirmed, randomization will be undertaken.  
 
5.5 
Electrocardiogram (ECG) 
 
Pre- and post-cardioversion electrocardiogram (ECG) data will be assessed at baseline.  Results from the ECG test 
will be entered onto the case report form (CRF).   
 
5.6 
Physical Examination and Medical History 
 
The screening evaluation will collect medical history data for assessment of inclusion/exclusion criteria, including 
coffee/other caffeinated product consumption history.  
 
 
5.7  
Targeted Medication Inventory 
 
Current/regular use (since the last study follow up) of a specific list of concomitant medications/therapies will be 
documented at baseline (post cardioversion) and at all follow-up visits.  Medication data will be collected by self-
report and electronic medical record on a CRF and will include type of medication.  The list of targeted 
medications/therapies includes AF-related medications (e.g., anticoagulants, antiarrhythmics, negative 
chronotropic agents). 
 
 
5.8. 
Specific Adverse Events 
 
Site personnel will review medical records to determine if any of the prespecified AEs occur: 
1. Any death 
2. Myocardial infarction 
3. Stroke/transient ischemic attack 
4. Heart failure exacerbation 
5. Hospitalization 
6. Syncope 
7. Emergency Room Visit 
 
 
 
6.0 Risks and Benefits of the Study 
 

 
 
 
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6.1   
Cardioversion Procedure 
 
The cardioversion procedure involves several risks, but each of these participants would experience these risks 
whether or not they choose to participate in DECAF or not, since inclusion is this trial requires already having a 
planned/scheduled cardioversion procedure.  The known risks have been shown to occur in less than 1% of cases 
and include adverse reaction from administered medications for sedation/anesthesia, lack of success, induction of 
another arrhythmia, skin burn, or stroke or transient ischemic attack. Potential benefits of cardioversion include 
reduction in symptoms (such as palpitations, shortness of breath, and dizzy spells), improvement in energy/well-
being, and strengthening of heart function (if AF is a major cause or contributor to weakened function). 
 
6.2   
Coffee Abstinence or Continuation 
 
Abstinence from coffee and other caffeine-related products may result in caffeine-withdrawal, symptoms of which 
can include headache, fatigue, anxiety, difficulty concentrating, depressed mood, irritability, tremors, and low 
energy. It is not clear what effect, if any, coffee has on AF and AF recurrence; this forms the rationale for the 
present study. Potential benefits of coffee abstention may therefore include a reduction in AF recurrence. 
Conversely, it may be possible that coffee consumption is beneficial and abstinence may result in a greater 
likelihood of AF recurrence.  
 
7.0  STUDY ROLES 
 
The DECAF study has been developed by the Principal Investigator at the University of California, San Francisco 
(UCSF).  The study investigators are committed to conducting this study in a uniform manner, adhering to the 
study protocol and the operations manual.  Standardization, supervision, and coordination of all procedures will be 
enhanced through peer review and quality control mechanisms. 
 
7.1   
Administrative Organization 
 
DECAF is organized and conducted by the coordinating center, the University of California San Francisco (UCSF) 
under the guidance of the Principal Investigator.  
 
7.2 
Enrolling Clinical Site 
 
The study will be conducted at 3 sites. 
 
The Coordinating Center for DECAF will be at the University of California, San Francisco. Another site is University 
of Adelaide, Adelaide, Australia. The final site is Sunnybrook Health Sciences Centre, Toronto, Canada.   
 
7.2.1   
Clinical Site Principal Investigator 
 
This study protocol will be conducted by the Principal Investigator and his staff.  The Principal Investigator has 
experience in and will be responsible for: 
• 
Conducting the study protocol in accordance with the signed agreement with the UCSF, the study protocol, all 
applicable FDA regulations (21 CFR Parts 50, 54, 56, 812), GCP guidelines, and any conditions of approval 
imposed by the IRB 
• 
Providing IRB Approval and an Approved Informed Consent  
• 
Screening and selecting appropriate participants 
• 
Collection and archiving of data obtained pursuant to the requirements of the study protocol during the 
course of the study and after the study has been completed 
 
It is acceptable for the Principal Investigator to delegate one or more of the above functions to an associate or co-
Investigator, however, the Principal Investigator remains responsible for the proper conduct of the study protocol, 
complying with the study protocol, and collecting all required data.  

 
 
 
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8.0  PROTOCOL DEVIATIONS 
 
Principal Investigators are required to adhere to the study protocol, applicable federal (national) or state/local, 
laws and regulations, and any conditions required by the IRB or applicable regulatory authorities. 
 
A protocol deviation is used to describe situations in which the clinical protocol was not followed.  All major 
deviations from the study protocol will be reported, as soon as possible, but no later than 10 working days of 
notification of the event.  In addition, all major deviations will be reported to the UCSF CC, as well as the local IRB 
as appropriate, per the IRB’s reporting requirements.  
 
9.0 QUALITY ASSURANCE AND DATA MANAGEMENT 
 
9.1 
Clinical Site Investigator and Coordinator Training 
 
Each investigator and coordinator will be trained on the study protocol and procedures to ensure accurate and 
consistent study methods are used study-wide and throughout the entire study duration.  Trainings will include 
review of the protocol, operations manual, CRFs, event reporting, and data management procedures.   
 
9.2 
Data Handling and Confidentiality 
 
Information about study participants will be kept confidential and managed according to the requirements of the 
Health Insurance Portability and Accountability Act of 1996 (HIPAA).  Those regulations require a signed patient 
authorization informing the patient of the following:  
• 
What protected health information (PHI) will be collected from study participants 
• 
Who will have access to that information and why 
• 
Who will use or disclose that information 
• 
The rights of a research participant to revoke their authorization for use of their PHI 
 
In the event that a participant revokes authorization to collect or use PHI, the Principal Investigator, by regulation, 
retains the ability to use all information collected prior to the revocation of participant authorization.  For 
participants that have revoked authorization to collect or use PHI, attempts should be made to obtain permission 
to collect at least vital status (i.e., that the participant is alive) at the end of their scheduled study follow-up. 
 
9.3  
Source Documents  
 
Complete study files will be kept in a secure location.  Participant files will include archives of completed CRFs and 
source documents.  The CRFs are the primary data collection instrument for the study and are considered source 
documents.  All data requested on the CRF will be recorded.  Source data also include original records of clinical 
findings, observations, or study measurement results (e.g.,  hospital records, clinical and office charts, laboratory 
notes, dispensing records, recorded data from automated instruments, and patient files).   
 
9.4  
Data Collection and Management 
 
The data will be compiled into the central study database at UCSF. Sites will collect and enter study data onto 
electronic CRFs via the online study database, REDCap.  The study data will be stored in the study database at UCSF 
and will be subjected to checks for completeness, consistency and validity.  Data entry will occur in a timely 
manner.   
 
For all procedures, clinical site personnel will only have access to their own site data.  
 

 
 
 
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9.5  
Data Monitoring 
 
[The investigators] will be responsible for monitoring procedures related to study conduct and data 
collection/reporting to ensure the quality and integrity of the study data.  A representative will check the 
completeness of participant study records, the accuracy of entries on the CRFs, the adherence to the protocol and 
to Good Clinical Practice, as per the DECAF Monitoring Guidelines.   
 
To ensure data quality, we will perform the following Quality Assurance procedures: after the first two participants 
are randomized and the study intervention is performed, 100% of inclusion/exclusion criteria and key baseline 
data points will be reviewed against source documentation collected from the site (such as the participant’s de-
identified initial EP H&P, procedure note and first follow-up EP note).  In addition, specified de-identified 
documentation will be requested from each site to perform source verification on a random 10% sample of key 
study data.  If during the course of the study the error rate exceeds a 5% threshold, the percentage of source 
verification will increase until control is demonstrated. 
 
10.0 STATISTICAL METHODS 
 
10.1  
Sample Size and Randomization 
 
The goal of this trial is the enroll a total of 200 participants (n=100 per treatment group). 
 
 
Assuming a 0.05 two-tailed alpha level, 1:1 randomization scheme, 50% recurrence rate in the absence of coffee, 
and potential 10% loss to follow-up, a sample size of n=200 (100 per arm) will provide approximately 80% power to 
detect a 1.63 times increased hazard of AF recurrence between the groups.  
 
The table below summarizes the minimum detectable relative hazards in Cox models with binary predictor, by 
baseline AF recurrence rate (RR) (rows) and Percent Lost to Follow up (LTFU) (columns) 
 
 
5% LTFU 
10% LTFU 
50% RR 
1.68 
1.69 
60% RR 
1.62 
1.63 
 
 
Randomization will be performed 1:1 with stratification across sites.  
 
10.2  
Intention-to-Treat (ITT) 
 
The main intention-to-treat (ITT) analysis set will include all randomized participants, whether or not they are 
compliant with the treatment allocation for this trial.  Every attempt will be made to collect data until the end of 
the follow-up period for all randomized participants and these data will be included as part of the main ITT 
analysis.  The analyses for the primary objective will be performed using the ITT dataset.   
 
Although substantial crossover is not anticipated, as treated and per protocol analyses will also be conducted if 
failure to comply with allocated treatment assignments occurs in more than 10% of cases or if there is a 
significantly different proportion of assignment adherence in one group compared to the other. 
 
 
11.0  PUBLICATION  
Any presentation/publication of any data from this study must be approved by the Principal Investigator prior to 
release.   

 
 
 
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12.0 ETHICAL CONSIDERATIONS 
 
This study is to be conducted according to US and international standards of Good Clinical Practice (FDA Title 21 
part 812 and International Conference on Harmonization guidelines), applicable government regulations, and 
Institutional research policies and procedures.   
 
12.1  
Institutional Review Board (IRB) and Ethics Committee (EC) Approval 
 
This protocol and any amendments will be submitted to a properly constituted independent IRB for each clinical 
site, in agreement with local legal prescriptions, for formal approval of the study conduct.  The decision of the IRB 
concerning the conduct of the study will be made in writing to the Principal Investigator. The Principal Investigator 
at each site should also provide a list of IRB members and their affiliates to the UCSF CC. 
 
12.2  
Informed Consent 
 
The investigator and/or study coordinator must explain to each participant the nature of the study, its purpose, 
the procedures involved, the expected duration, the potential risks and benefits involved, and any discomfort it 
may entail.  Each participant must be informed that participation in the study is voluntary and that he/she may 
withdraw from the study at any time and that withdrawal of consent will not affect his/her subsequent medical 
treatment or relationship with the treating physician.  
 
This informed consent should be given by means of a standard written statement, written in non-technical 
language.  The subject should read and consider the statement before signing and dating it, and should be given a 
copy of the signed document.  If the participant cannot read or sign the document, oral presentation may be made 
or signature given by the participant’s legally appointed representative, if witnessed by a person not involved in 
the study, mentioning that the participant could not read or sign the documents.  No participant can enter the 
study before his/her informed consent has been obtained.  
 
The informed consent form must be submitted by the investigator for IRB approval.  An informed consent 
template will be provided to all of the clinical sites for their use.  Any changes to the template consent form 
suggested by the Investigator must be agreed to by the UCSF CC before submission to the local IRB, and a copy of 
the approved version must be provided to UCSF CC after IRB approval. 
 
12.3  
Declaration of Helsinki 
 
The investigator must conduct the trial in accordance with the Declaration of Helsinki.   
 

 
 
 
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 SUMMARY OF PROTOCOL CHANGES 
 
 
Protocol Date 
Description of Change  
Brief Rationale 
Sept 5, 2021 
Original version 
N/A 
Oct 19, 2021 
Study duration changed from 12 to 6 months 
 
To facilitate recruitment given frequent 
reluctance of patients to abstain from coffee 
 
Addition of Month-1 follow-up visit 
 
To add an earlier timepoint than Month-3 given 
reduction in study duration to 6 months 
 
Amendment of inclusion criteria: “sustained AF or 
atrial flutter (provided patient has a history of AF)”  
 
Given previous lack of reference to atrial flutter, 
to clarify that patients in flutter at time of 
cardioversion were eligible if they also had a 
history of AF 
 
Amendment of exclusion criteria: “recent/planned AF 
ablation within 6 months”  
Previously was 12 months - change to reflect 
reduction in study duration to 6 months 
 
Correction of remaining references to previous study 
title to “DECAF” throughout document 
Completion of prior change not undertaken 
throughout document in some places 
January 19, 2023 
Addition of second site: University of Adelaide 
To facilitate recruitment 
 
Clarification of primary objective: “time to first 
confirmed AF recurrence and/or Aflutter recurrence 
following cardioversion” 
Given previous lack of reference of atrial flutter, 
to clarify that either recurrent AF or flutter 
would fulfil primary endpoint  
October 9, 2023 
Addition of previously approved Month-1 follow-up 
visit throughout document where missing 
Completion of prior change not undertaken 
throughout document in some places 
 
Addition of option to call & enroll patients remotely 
within 1 week of cardioversion if clinical care did not 
allow time for coordinator to approach during hospital 
visit 
To facilitate recruitment as busy clinical care 
settings were preventing many eligible patients 
being approached by coordinators before 
cardioversion 
 
Amendment of exclusion criteria: “recent/planned AF 
ablation within 3 months” 
Previously was 6 months - to facilitate 
recruitment as many otherwise eligible patients 
had had ablation within 6 months 
May 31, 2024 
Addition of third site: Sunnybrook Health Sciences 
Centre 
To facilitate recruitment 
 
Amendment of secondary objectives: removal of AF 
and coffee abstinence symptom assessments  
 
These secondary assessments were initially 
planned at the time of initial study design but 
due to practical constraints were not collected 
 
Amendment of inclusion criteria: “life expectancy of at 
least 6 months” 
 
Previously was 1 year – change to reflect prior 
reduction in study duration to 6 months 
 
Amendment of  “Lost to Follow-Up” procedure: 
clarified that medical record review was also utilized in 
addition to physician/healthcare professional contact 
to confirm AF recurrence status 
 
Clarification that, in addition to contacting 
physician/healthcare professional, medical 
record use was approved to confirm AF 
recurrence status if patient did not attend 
follow up visits 
 
Removal of SF-36, hrQOL, and physical activity 
questionnaires 
 
These assessments were initially planned at the 
time of initial study design but due to practical 
constraints these data were not collected 
 
Removal of Section 5.9 Targeted Medical Care 
Utilization  
 
The collection of these data are already 
described in Section 5.10 Adverse Event 
Collection 
 
Amendment of Section 5.7 Targeted Medication 
Inventory: reference to dosage and frequency 
removed 
Clarified that medication type was collected but 
not dosage or frequency 

 
 
 
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June 12, 2025 
Clarification of primary objective: “time to first 
confirmed clinical recurrence of AF recurrence and/or 
atrial flutter recurrence, or device-detected 
recurrence lasting longer than 30 seconds” –  
Given previous lack reference to device-
detected recurrence, to clarify that device data 
was also reviewed and a threshold of 30 
seconds utilized 
 
Amendment of secondary objectives: addition of 
adverse events and separate AF/atrial flutter 
assessment, and removal of other arrhythmia 
assessment  
 
Clarification that adverse events and 
assessment of AF and atrial flutter recurrence 
separately are prespecified secondary 
endpoints, and that collection of other 
arrhythmias was not systematically undertaken 
due to practical constraints and thus removed 
 
Amendment of Section 3.0 Study Treatment: addition 
that participants could consume or abstain from 
coffee at their discretion following primary endpoint 
being met, end of study (6 months), or study 
withdrawal 
Clarification that patients could consume or 
abstain at their discretion after their 
involvement in the trial was complete 
 
Miscellaneous: removal of day 1 study visit that was 
not undertaken, addition of heart failure exacerbation 
that was collected as an adverse event, removal of 
remaining references to coffee abstinence symptom 
assessment, clarification of wording, minor 
grammatical errors 
Correction of several minor errors and 
clarification of wording throughout document 
 
 

 
 
 
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BIBLIOGRAPHY 
 
 
 
 
1. 
Miyasaka, Y., et al., Secular Trends in Incidence of Atrial Fibrillation in Olmsted County, Minnesota, 1980 to 
2000, and Implications on the Projections for Future Prevalence. Circulation, 2006. 114(2): p. 119-25. 
2. 
Rienstra, M., et al., Symptoms and Functional Status of Patients With Atrial Fibrillation State of the Art and 
Future Research Opportunities. Circulation, 2012. 125(23): p. 2933-2943. 
3. 
Gallagher, C., et al., Increasing trends in hospitalisations due to atrial fibrillation in Australia from 1993 to 
2013. Heart, 2019. 105(17): p. 1358-1363. 
4. 
O'Keefe, J.H., et al., Effects of habitual coffee consumption on cardiometabolic disease, cardiovascular 
health, and all-cause mortality. J Am Coll Cardiol, 2013. 62(12): p. 1043-1051. 
5. 
Voskoboinik, A., J.M. Kalman, and P.M. Kistler, Caffeine and Arrhythmias: Time to Grind the Data. JACC 
Clin Electrophysiol, 2018. 4(4): p. 425-432. 
6. 
McCusker, R.R., B.A. Goldberger, and E.J. Cone, Caffeine content of specialty coffees. J Anal Toxicol, 2003. 
27(7): p. 520-2. 
7. 
Wilhelmsen, L., A. Rosengren, and G. Lappas, Hospitalizations for atrial fibrillation in the general male 
population: morbidity and risk factors. J Intern Med, 2001. 250(5): p. 382-9. 
8. 
Xu, J., et al., Intermittent Nonhabitual Coffee Consumption and Risk of Atrial Fibrillation: The Multi-Ethnic 
Study of Atherosclerosis. J Atr Fibrillation, 2019. 12(1): p. 2205. 
9. 
Frost, L. and P. Vestergaard, Caffeine and risk of atrial fibrillation or flutter: the Danish Diet, Cancer, and 
Health Study. Am J Clin Nutr, 2005. 81(3): p. 578-82. 
10. 
Shen, J., et al., Dietary factors and incident atrial fibrillation: the Framingham Heart Study. Am J Clin Nutr, 
2011. 93(2): p. 261-6. 
11. 
Larsson, S.C., et al., Coffee consumption is not associated with increased risk of atrial fibrillation: results 
from two prospective cohorts and a meta-analysis. BMC Med, 2015. 13: p. 207. 
12. 
Klatsky, A.L., et al., Coffee, caffeine, and risk of hospitalization for arrhythmias. Perm J, 2011. 15(3): p. 19-
25. 
13. 
Mostofsky, E., et al., Risk of atrial fibrillation associated with coffee intake: Findings from the Danish Diet, 
Cancer, and Health study. Eur J Prev Cardiol, 2016. 23(9): p. 922-30. 
14. 
Casiglia, E., et al., Caffeine intake reduces incident atrial fibrillation at a population level. Eur J Prev 
Cardiol, 2018. 25(10): p. 1055-1062. 
15. 
Kim, E.J., et al., Coffee Consumption and Incident Tachyarrhythmias: Reported Behavior, Mendelian 
Randomization, and Their Interactions. JAMA Intern Med, 2021. 
16. 
Conen, D., et al., Caffeine consumption and incident atrial fibrillation in women. Am J Clin Nutr, 2010. 
92(3): p. 509-14. 
17. 
Bodar, V., et al., Coffee Consumption and Risk of Atrial Fibrillation in the Physicians' Health Study. J Am 
Heart Assoc, 2019. 8(15): p. e011346. 
18. 
Bazal, P., et al., Caffeinated coffee consumption and risk of atrial fibrillation in two Spanish cohorts. Eur J 
Prev Cardiol, 2021. 28(6): p. 648-657. 
19. 
Caldeira, D., et al., Caffeine does not increase the risk of atrial fibrillation: a systematic review and meta-
analysis of observational studies. Heart, 2013. 99(19): p. 1383-9. 
20. 
Cheng, M., et al., Caffeine intake and atrial fibrillation incidence: dose response meta-analysis of 
prospective cohort studies. Can J Cardiol, 2014. 30(4): p. 448-54. 
21. 
Yuan, S. and S.C. Larsson, No association between coffee consumption and risk of atrial fibrillation: A 
Mendelian randomization study. Nutr Metab Cardiovasc Dis, 2019. 29(11): p. 1185-1188. 
22. 
Lemery, R., et al., A prospective placebo controlled randomized study of caffeine in patients with 
supraventricular tachycardia undergoing electrophysiologic testing. J Cardiovasc Electrophysiol, 2015. 
26(1): p. 1-6. 
23. 
Mattioli, A.V., et al., The relationship between personality, socio-economic factors, acute life stress and the 
development, spontaneous conversion and recurrences of acute lone atrial fibrillation. Europace, 2005. 
7(3): p. 211-20. 

 
 
 
DECAF Protocol 
 
 
NCT05121519 
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                           Page 21 of 21 
24. 
Mattioli, A.V., et al., Influence of coffee and caffeine consumption on atrial fibrillation in hypertensive 
patients. Nutr Metab Cardiovasc Dis, 2011. 21(6): p. 412-7. 
25. 
Dixit, S., et al., Consumption of Caffeinated Products and Cardiac Ectopy. J Am Heart Assoc, 2016. 5(1). 
26. 
Groh, C.A., et al., Patient-reported triggers of paroxysmal atrial fibrillation. Heart Rhythm, 2019. 16(7): p. 
996-1002. 
27. 
Hughes, J.R., G. Amori, and D.K. Hatsukami, A survey of physician advice about caffeine. J Subst Abuse, 
1988. 1(1): p. 67-70. 
28. 
January, C.T., et al., 2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the 
Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American 
Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society in Collaboration 
With the Society of Thoracic Surgeons. Circulation, 2019. 140(2): p. e125-e151. 
29. 
Hindricks, G., et al., 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed 
in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): The Task Force for the 
diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed 
with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC. Eur Heart J, 
2021. 42(5): p. 373-498. 
30. 
Collins, R. and S. MacMahon, Reliable assessment of the effects of treatment on mortality and major 
morbidity, I: clinical trials. Lancet, 2001. 357(9253): p. 373-80. 
31. 
MacMahon, S. and R. Collins, Reliable assessment of the effects of treatment on mortality and major 
morbidity, II: observational studies. Lancet, 2001. 357(9254): p. 455-62. 
 

 
 
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DECAF 
 
Does Eliminating Coffee Avoid Fibrillation? 
 
A randomized controlled trial to assess abstinence of coffee compared to continued 
consumption on recurrent atrial fibrillation following cardioversion  
 
 
Author(s): 
Gregory M. Marcus, MD, MAS 
Principal Investigator, University of California, San Francisco 
 
Christopher X. Wong, MBBS, PhD 
Cardiac Electrophysiologist, The University of Adelaide 
 
Catherine Lee, PhD 
Biostatistician, University of California, San Francisco 
 
Document type: 
Statistical Analysis Plan  
Version: 
1.0 
Release date: 
June 12, 2025 
 
 
 
 
 
 
 
 
 
 

 
 
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                           Page 2 of 7 
TABLE OF CONTENTS  
  
1.0  STUDY OVERVIEW AND RATIONALE ...................................................................................................................... 3 
1.1.  SCOPE FOR ANALYSIS ....................................................................................................................................... 3 
2.0  STUDY AIMS AND ENDPOINTS ............................................................................................................................... 3 
4.1 
ALLOCATION .............................................................................................................................................. 5 
4.2  
BLINDING ................................................................................................................................................... 5 
5.0   SAMPLE SIZE AND POWER CALCULATIONS ........................................................................................................... 5 
6.0 STATISTICAL METHODS ........................................................................................................................................... 5 
6.1   
PRIMARY ENDPOINT ANALYSIS .................................................................................................................. 6 
6.2   
SECONDARY ENDPOINT ANALYSIS ............................................................................................................. 6 
BIBLIOGRAPHY .............................................................................................................................................................. 7 
 
 
 

 
 
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1.0  STUDY OVERVIEW AND RATIONALE  
 
This study is an investigator-initiated, prospective, open-label, randomized clinical trial of coffee 
abstention compared to continued caffeinated coffee consumption in patients with atrial fibrillation 
(AF). It will be conducted at multiple clinical sites in the United States, Australia, and Canada. The goal is 
to enroll and randomize two-hundred (200) adult men and women.  
 
AF is the most common, sustained heart rhythm disorder experienced by humans. Coffee is one of the 
most ubiquitously consumed substances worldwide. Given both the increasing population impact of AF 
and the widespread use of coffee in society, determining any benefit, risk, or lack of any effect of coffee 
on AF would be of great interest to physicians, scientists, and individual consumers. 
 
Prior observational studies have evaluated the role of chronic coffee consumption and incident AF with 
varied results. [1-3]  However, established notions exist that coffee and caffeine contribute to AF and/or 
trigger AF episodes. In a large study of symptomatic patients with paroxysmal AF, caffeine was reported 
as the second most common triggering factor in almost one-third of individuals.[4]  Prior surveys of 
physicians have also suggested reductions in caffeine to assist with arrhythmias.[5] Conversely, 
professional society guidelines either do not discuss coffee or caffeine[6] or suggest they are unlikely to 
contribute based on recent studies.[7] Interestingly, observational studies generally suggest that 
caffeinated coffee has no association with AF, or even may be associated with a lower risk of AF.[8] [2, 3, 
9] 
 
A key limitation of existing data on the effects of coffee and caffeine on AF has been their observational 
nature. This trial thus seeks assess the effect of random allocation to coffee abstinence compared to 
continued caffeinated coffee consumption in patients undergoing cardioversion for AF or atrial flutter, 
with patients being followed up for recurrent episodes of AF. 
 
1.1.  SCOPE FOR ANALYSIS 
 
The trial analyses will assess the effect of coffee abstinence compared to continued caffeinated coffee 
consumption on AF recurrence in patients undergoing cardioversion.  
 
2.0  STUDY AIMS AND ENDPOINTS 
 
Hypothesis: Coffee abstinence will result in a lower recurrence of AF following cardioversion compared to 
continued caffeinated coffee consumption (mention of coffee for the SAP refers to caffeinated coffee; 
those randomized to avoid coffee were indeed randomized to avoid all coffee).  
 
Primary endpoint: 
• 
The number of people with first confirmed clinical recurrence of AF or atrial flutter, or device-
detected recurrence lasting longer than 30 seconds, following cardioversion in the coffee 
abstinence group compared to the continued caffeinated coffee consumption group analyzed as 
a time-to-event outcome. 
 
Secondary endpoints: 
• 
Adverse events before censorship, including myocardial infarction, stroke or transient ischemic 
attack, heart failure exacerbation, syncope, emergency department visit, hospitalization, and 
death 

 
 
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• 
Atrial flutter and atrial fibrillation separately as incident outcomes 
 
 
3.0  STUDY DESIGN 
 
This study is a multicenter, investigator-initiated, prospective, open-label, randomized clinical trial. After 
screening and eligibility has been determined, participants will be randomized after successful 
cardioversion. Follow-up visits will occur at: Month 1, Month 3, and Month 6. See the DECAF protocol 
for the schedule of evaluations, data sources, and windows for each of the study visits. Clinical sites will 
make every possible effort to ensure that each study visit is conducted within the specified window.  
 
4.0 STUDY POPULATION  
 
The target population for this trial is adults in the United States, Australia, or Canada with AF.  
 
Potential participants will be identified at each clinical site from lists of patients with a planned and/or 
scheduled direct current electrical cardioversion. Eligibility for the study will be confirmed, using the 
inclusion/exclusion criteria noted below, prior to randomization after successful cardioversion.  
 
INCLUSION CRITERIA 
 
Patients must meet all of the following to be eligible: 
1. Men or women ≥ 21 years of age 
2. Sustained atrial fibrillation or atrial flutter (provided patient has history of atrial fibrillation) 
3. Planned/scheduled direct current electrical cardioversion 
4. Consumption greater than or equal to one cup of caffeinated coffee per day sometime in the past 5 
years  
5. Willing and able to comply with coffee abstinence or continuation of caffeinated coffee for at least 6 
months 
6. Life expectancy of at least 6 months 
7. Willing and able to return and comply with scheduled follow up visits 
8. Willing and able to provide written informed consent 
 
EXCLUSION CRITERIA 
 
Patients will be excluded if they meet any of the following: 
1. Established allergy or adverse reaction to coffee  
2. Stated inability to comply with coffee abstinence or continuation 
3. Atrial fibrillation ablation in preceding 3 months or planned in the next 3 months 
4. Recent cardiothoracic surgery in preceding 3 months 
5. Pregnancy or desire to get pregnant within next 6 months. 
6. Current enrollment in an investigation or study of a cardiovascular device or investigational drug 
that would interfere with this study 
7. Any other criteria, which would make the patient unsuitable to participate in this study as 
determined by the Principal Investigator (e.g., an uncontrolled drug and/or alcohol addiction) 
 
 
 

 
 
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4.1 
ALLOCATION 
 
After successful cardioversion, participants will be randomized (1:1) to one of the two arms: coffee 
abstinence or continued caffeinated coffee consumption.  
 
The DECAF study-wide allocation scheme will be created by a statistician prior to the start of the trial. 
Randomization will be performed with 1:1 with stratification across sites. 
 
Sites will be instructed to randomize a participant as follows: 
- 
After primary eligibility has been confirmed 
- 
After all screening measures have been performed 
- 
As soon as possible after successful cardioversion 
 
Participants who completed primary eligibility and screening measures but did not have a successful 
cardioversion (such as due to inability to convert AF or documented early recurrence of AF prior to 
leaving the procedure room) will be excluded prior to randomization.  
 
4.2  
BLINDING 
 
Due to the nature of the intervention, it is not practical to have participants blinded to their randomized 
allocation.   
 
5.0   SAMPLE SIZE AND POWER CALCULATIONS 
 
The goal is to enroll a total of 200 participants (n=100 per treatment group) study-wide. 
 
The sample size is based on the following assumptions: (1) a 50% incidence of AF recurrence; (2) 10% 
loss to follow-up; and (3) 0.05 two-tailed alpha level. Under these assumptions, a sample of 200 
individuals randomized 1:1 to either coffee abstention or continued caffeinated coffee consumption will 
provide 80% power to detect a 1.63 times increased hazard of AF between the groups.  
 
6.0 STATISTICAL METHODS 
 
All analyses will be conducted upon completion of data collection and database lock. No interim 
analyses are planned. 
 
The primary analysis will be by intention-to-treat (ITT), according to randomized allocation, without 
regard to participant compliance with this randomized allocation. Every attempt will be made to collect 
data for both primary and secondary endpoints until the end of the six month follow-up period for all 
randomized participants, and all data will be included as part of the primary ITT analysis. 
 
Although substantial crossover is not anticipated, as treated and per protocol analyses will be conducted 
if failure to comply with the randomized allocation occurs in more than 10% of all participants or if there 
is a significantly different proportion of assignment adherence in one group compared to the other. The 
per protocol analyses will be restricted to a sub-sample excluding all the protocol violators, and adjust 
for any baseline factors that are imbalanced (P<0.1) in the per-protocol sub-sample. 
 
Patient baseline characteristics will be summarized overall and by randomization assignment. 
Continuous variables will be summarized using means and standard deviations (SD) for normally 

 
 
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distributed measures or medians and quartiles for non-normally distributed measures. Categorical 
variables will be summarized using contingency tables that display counts and percentages. 
 
All tests will be two-sided with a 0.05-level of significance. Adjustment for multiple comparisons will not 
be used. 
 
6.1   
PRIMARY ENDPOINT ANALYSIS 
 
The primary endpoint, defined as the clinical recurrence of AF or device-detected AF lasting longer than 
30 seconds, will be analyzed as a time-to-event outcome.  Follow-up time for participants who do not 
experience the primary endpoint will be censored at the time of study withdrawal or end of study 
(month 6). Kaplan-Meier plots will be used descriptively to compare the survival distributions of the 
primary endpoint by randomization arm. Cox proportional hazards regression models including the 
randomization assignment will be used to formally analyze the primary endpoint (AF recurrence). These 
models will also include study site, used in the randomization procedure as a stratification factor, and  
additionally baseline patient characteristics in sensitivity analyses. Point estimates and Wald-based 95% 
confidence intervals and p-values will be reported. The primary ITT analysis will include all participants 
regardless of compliance with randomized allocation.  
 
 
6.2   
SECONDARY ENDPOINT ANALYSIS  
 
Prespecified secondary endpoints include atrial flutter and atrial fibrillation separately as incident 
outcomes, and adverse events before censorship including myocardial infarction, stroke or transient 
ischemic attack, heart failure exacerbation, emergency department visit, syncope, hospitalization, and 
death. Kaplan-Meier plots will be used to describe the survival distributions of secondary time-to-event 
outcomes (e.g., death) by trial arm and Cox hazard regression will be used for analysis. Continuous 
secondary endpoints will be described by randomization assignment using means and SDs, or medians 
and quartiles and categorical endpoints will be summarized using counts and percentages.  Generalized 
linear models, which accommodate a range of outcome types including dichotomous, continuous, and 
counts, will be used for analysis. Randomization assignment will be included in all models, as well as 
study site used as a stratification factor in the randomization procedure. Additional models will adjust 
for the baseline patient characteristics in sensitivity analyses.  

 
 
DECAF Statistical Analysis Plan 
 
 
NCT05121519 
 
 
 
 
DECAF SAP V1.0 – June 12 2025                              
 
                           Page 7 of 7 
 BIBLIOGRAPHY 
 
 
1. 
Caldeira, D., et al., Caffeine does not increase the risk of atrial fibrillation: a systematic review and meta-
analysis of observational studies. Heart, 2013. 99(19): p. 1383-9. 
2. 
Cheng, M., et al., Caffeine intake and atrial fibrillation incidence: dose response meta-analysis of 
prospective cohort studies. Can J Cardiol, 2014. 30(4): p. 448-54. 
3. 
Larsson, S.C., et al., Coffee consumption is not associated with increased risk of atrial fibrillation: results 
from two prospective cohorts and a meta-analysis. BMC Med, 2015. 13: p. 207. 
4. 
Groh, C.A., et al., Patient-reported triggers of paroxysmal atrial fibrillation. Heart Rhythm, 2019. 16(7): p. 
996-1002. 
5. 
Hughes, J.R., G. Amori, and D.K. Hatsukami, A survey of physician advice about caffeine. J Subst Abuse, 
1988. 1(1): p. 67-70. 
6. 
January, C.T., et al., 2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the 
Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American 
Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society in Collaboration 
With the Society of Thoracic Surgeons. Circulation, 2019. 140(2): p. e125-e151. 
7. 
Hindricks, G., et al., 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed 
in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): The Task Force for the 
diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed 
with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC. Eur Heart J, 
2021. 42(5): p. 373-498. 
8. 
Kim, E.J., et al., Coffee Consumption and Incident Tachyarrhythmias: Reported Behavior, Mendelian 
Randomization, and Their Interactions. JAMA Intern Med, 2021. 181(9): p. 1185-1193. 
9. 
Krittanawong, C., et al., Is caffeine or coffee consumption a risk for new-onset atrial fibrillation? A 
systematic review and meta-analysis. Eur J Prev Cardiol, 2020: p. 2047487320908385.