Lifestyle triggers in
paroxysmal atrial
fibrillation: insights from
the 2021 AHA meeting
Michael Ruiz MD MSc
PGY4 Cardiology Resident
michael.ruiz@mail.utoronto.ca
@dobutamike
Disclosures
• None
Overview
• Triggers of episodes of paroxysmal atrial fibrillation (AF)
• N-of-1 studies
• Updates from AHA 2021
• I-STOP-AFib
• CRAVE
• Summary
Triggers of episodes of atrial fibrillation
What lifestyle modifications do you advise for your patients to
avoid paroxysmal AF episodes?
Consensus Statement on Lifestyle and Risk Factor
Modification for Reduction of Atrial Fibrillation: AHA 2020
Chung et al. Circulation 2020
Consensus Statement on Lifestyle and Risk Factor
Modification for Reduction of Atrial Fibrillation: AHA 2020
Chung et al. Circulation 2020
What about caffeine?
• Caffeine is a methylxanthine that exerts its
effects on the body through inhibition of
adenosine receptors and phosphodiesterase
• Effects on the heart are mainly mediated
through phosphodiesterase inhibition, leading to
increased cAMP, increased intracellular calcium
and stimulatory effects
• Historically caffeine restriction has been
recommended in the settings of arrhythmias
Caffeine for the Sustainment of Mental Task Performance:
Formulations for Military Operations. Chapter 2.
Caffeine as a trigger for episodes of AF
Chung et al. Circulation 2020
N-of-1 studies
• “Cross-over” trials in which one participant receives both the
experimental and control treatments at different points in time
• Two or more treatment arms can be assessed
• Participant is effectively their own control
Eligibility,
randomization
Treatment A
Washout and
crossover
Treatment B
Washout and
crossover
Outcome
measured
Treatment C
Washout and
crossover
Outcome
measured
Etc.
Outcome
measured
Lillie et al. Per Med 2011
N-of-1 studies
Benefits
Challenges
• Reduced heterogeneity
between treatment and
control groups
• Sequencing
• Useful when outcome
measures are more
“subjective”
• Wash out periods
• Randomization can be
incorporated
• Lack of familiarity and
utilization in clinical
medicine
• Carry over effects
• Blinding
Lillie et al. Per Med 2011
I-STOP-AFib: Rationale and Design
• Designed by investigators and patients in the 2014 Health eHeart
Alliance Patient-Powered Research Summit, a brainstorming session
funded by the Patient-Centered Outcomes Research Institute
• N-of-1 clinic trial, with randomization into trigger vs. monitoring arms
• Goal: investigate if education on the relationship between patient
selected triggers and actual AF episodes resulted in better quality of
life metrics
Marcus et al. JAMA Cardiol 2021
I-STOP-AFib: Rationale and Design
• Inclusion criteria:
1. Symptomatic, paroxysmal AF
2. Owned a smart phone
3. Interested in testing a trigger they could expose themselves to and
withhold
• Exclusion criteria:
1. Change in AF treatment planned in next 6 months (e.g. change in
medication, planned ablation)
2. Did not speak English
3. Underwent AV node ablation
Marcus et al. JAMA Cardiol 2021
I-STOP-AFib: Rationale and Design
• Treatment arms:
• Individualized trigger testing (N-of-1 arm)
• Monitoring for AF without trigger testing (control)
• Participants could choose their trigger
• Outcomes:
1. Primary: Atrial fibrillation effect on quality of life questionnaire
(AFEQT)
2. Secondary: Mobile ECG daily and when symptomatic
Marcus et al. JAMA Cardiol 2021
I-STOP-AFib: Rationale and Design
• Participants in the trigger arm underwent six 1-week periods of
trigger avoidance or exposure, followed by individualized feedback
and 4 weeks of monitoring
• Daily text messages to remind trigger avoidance or exposure, assess
degree of exposure
• Participants in the monitoring only arm received reminders to monitor
for 10 weeks
Reminders
Trigger Arm
Monitor Arm
Feedback on trigger
exposure and episodes of AF
ECGs
ON
OFF
ON
OFF
OFF
ON
MONITORING FOR SYMPTOMS, DAILY ECG
10 weeks
AFEQT assessment
4 weeks
MONITORING
I-STOP-AFib: Rationale and Design
• Triggers selected:
•
•
•
•
•
•
•
•
•
•
Caffeine (n = 53)
Alcohol (n = 43)
Reduced sleep (n = 31)
Exercise (n = 30)
Lying on left side (n = 17)
Dehydration (n = 10)
Large meals (n = 7)
Cold food or drink (n = 5)
Specific diets (n = 6)
Customized triggers (n = 4)
Marcus et al. JAMA Cardiol 2021
I-STOP-AFib: Rationale and Design
• Statistics:
• Probability a trigger influenced AF was determined through daily AF
was analyzed as a binary event using a bayesian generalized linear
model, adjusted for autocorrelation using noninformative prior
distributions with intention-to-treat and per-protocol approaches
• Days on which AF was unreported were analyzed in 2 ways: by
dropping the missing days and by imputing no events to those days
• Odds ratio (OR) with 95% not crossing 1 and one-tailed posterior
probability (Pr) greater than 0.975 were considered significant
Marcus et al. JAMA Cardiol 2021
I-STOP-AFib: Results
• Of 2987 individuals, 740 were eligibile, 684 consented, 499
began randomization activities, and 446 completed activities
required for randomization (intention-to-treat)
• Of 446 participants who initiated their randomized assignment,
320 (72%) completed all study activities (per-protocol)
Marcus et al. JAMA Cardiol 2021
I-STOP-AFib: Results
I-STOP-AFib: Results
• No differences in
primary outcome of
quality of life after
receiving feedback
for trigger testing
• N.B. 58 is
considered
moderate AF
burden
Marcus et al. JAMA Cardiol 2021
I-STOP-AFib: Results
• Secondary outcome: Individuals with n of 1 testing had 40%
fewer AF events compared to monitoring group
• This difference was driven by alcohol, dehydration and exercise
triggers (adjusted relative risk, 0.60; 95% CI, 0.43-0.83;
P<0.001)
Marcus et al. JAMA Cardiol 2021
I-STOP-AFib: Limitations
• N-of-1 design: motivated patients, not blinded, self identified
triggers, self report symptoms
• Monitoring mechanisms: self triggered ECG
• Attrition during study: differences found in individual triggers
with intention to treat but no per protocol
Marcus et al. JAMA Cardiol 2021
I-STOP-AFib: Conclusions
• First study to incorporate an N-of-1 study design and
randomization to study triggers of episodes of AF
• Educating patients on triggers (that have been validated
through N-of-1 testing) resulted in lower rates of AF but no
difference in quality of life
• Only alcohol was associated with higher rates of AF, unclear if
this was due to underpowering
Marcus et al. JAMA Cardiol 2021
Time to take a sip…
Coffee and Real-time Atrial and
Ventricular Ectopy (CRAVE)
• Goal: in healthy individuals without arrhythmia, to assesss the
association between caffeine consumption and atrial and
ventricular activity
• Inclusion criteria: Healthy individuals (median age 38), had
smart phone, drink coffee or espresso, willing to abstain when
requested, willing to provide saliva sample for genetic analysis
• Exclusion criteria: taking anti-arrhythmic, BB, CCB, PPM or
ICD
Marcus et al. AHA 2021 (data not yet published)
Coffee and Real-time Atrial and
Ventricular Ectopy (CRAVE)
• N-of-1 trial design where 100 participants were asked to
consume caffeine on one day and then avoid caffeine the next
day for 14 days total
• Atrial and ventricular ectopy were assessed with continuous
ECG (Zio patch)
• Other measures included continuous glucose monitor and Fitbit
monitoring to assess daily activity (steps) and sleep
Marcus et al. AHA 2021 (data not yet published)
Marcus et al. AHA 2021 (data not yet published)
Coffee and Real-time Atrial and
Ventricular Ectopy (CRAVE)
• Assignment to coffee consumptions was associated with:
1.
2.
3.
4.
54% increase in PVCs (RR 1.54, 95% CI 1.19-2.0, p = 0.001)
36 fewer minutes of sleep per night
1,058 additional Fitbit-based steps per days
Each additional cup of coffee was associated with 3% more daily
premature atrial contractions and 18 fewer minutes asleep per night
5. No significant differences in glucose levels and no increase in atrial
arrhythmias were observed.
• Researchers did note that faster caffeine metabolizers
experienced heightened PVCs, while slower caffeine
metabolizers experienced the greatest impact on sleep
Marcus et al. AHA 2021 (data not yet published)
Summary
• Lifestyle counselling is an important aspect of AF management
• Caffeine is a common patient-identified trigger for AF, and
restriction has historically been advised, though evidence is not
supportive of this practice
• N-of-1 studies can be useful to study exposures on effects that
are more challenging to assess in classic RCTs (e.g. quality of
life)
Summary
• I-STOP-AF looked correlating self-identified AF triggers with
episodes of AF, then used that information to educate patients
on whether they should seek or avoid them, and found this did
reduce AF burden but did not affect quality of life
• CRAVE looked at the effect caffeine consumption in healthy
individuals and found caffeine consumption was associated with
increased PVC burden but did not have an effect on atrial
arrhythmias
Chung et al. Circulation 2020
Chung et al. Circulation 2020
References
1.
Chung MK et al. Lifestyle and Risk Factor Modification for Reduction of Atrial Fibrillation: A
Scientific Statement From the American Heart Association. Circulation. 2020 Apr
21;141(16):e750-e772.
2.
Lillie EO et al. The n-of-1 clinical trial: the ultimate strategy for individualizing medicine?. Per
Med. 2011;8(2):161-173.
3.
Institute of Medicine (US) Committee on Military Nutrition Research. Caffeine for the Sustainment
of Mental Task Performance: Formulations for Military Operations. Washington (DC): National
Academies Press (US); 2001. 2, Pharmacology of Caffeine. Available from:
https://www.ncbi.nlm.nih.gov/books/NBK223808/
4.
Marcus GM et al. Individualized Studies of Triggers of Paroxysmal Atrial Fibrillation: The I-STOPAFib Randomized Clinical Trial. JAMA Cardiol. 2021 Nov 14:e215010.
5.
Marcus GM et al. CRAVE trial. AHA Meeting 2021. Available from: http://clinicaltrialresults.org/drgregory-marcus-and-dr-serge-korjian-discuss-crave-coffee-and-real-time-atrial-and-ventricularectopy/
Thank you
michael.ruiz@mail.utoronto.ca