Alcoholic Drinks Stand Out in Novel Trial Exploring AF Triggers

November 14, 2021

People with paroxysmal atrial fibrillation (AF) who explored potential triggers of their arrhythmia, and used them to make lifestyle changes, went on to show a 40% decline in subjectively experienced bouts of AF in a randomized trial with an unusual design.

But the study didn't provide evidence that the drop in self-reported AF necessarily improved their quality of life, its primary endpoint. Nor was there any apparent relationship between potential triggers and AF episodes detected less subjectively using a handheld electrocardiography (ECG) monitor.

Although the study — called I-STOP-AFib — has limitations, its results jibe with alcohol intake's increasingly appreciated status as a potential AF trigger. It was alone among many possible triggers tested in showing a consistent association with self-reported AF.

As a result, the study offers no support for such a link between the arrhythmia and caffeine intake, sleep deprivation, dehydration, exercise, or other conditions sometimes perceived as triggers, observed principal investigator Gregory M. Marcus, MD, MAS, University of California, San Francisco, when presenting results at the virtual American Heart Association (AHA) Scientific Sessions 2021. He is also lead author on the study's simultaneous publication in JAMA Cardiology.

The I-STOP-AFib trial was unusual in part for its virtual design, in which participants followed instructions and tracked AF episodes — both perceived and detected by the handheld ECG device — through a smartphone application. It also featured an N-of-1 randomized comparisons of different weeks in which individuals were or were not exposed to their self-selected trigger.

Such patients following their own weekly personalized randomization were compared to an entirely separate randomized control arm of the trial, in which patients simply tracked any ECG-monitored and self-perceived AF episodes.

Current Use in Patients

Although wearable and smartphone-based ECG recorders are increasingly popular for AF screening, Marcus said the devices may be especially helpful for validating whether a person's symptoms are actually caused by AF.

"I have actually suggested to some of my patients that they run some of these experiments," he said at a media briefing on I-STOP-AFib before his main presentation of the trial. The demonstration might help patients recognize that some perceived triggers actually do not induce AF.

Allowing patients to determine on their own whether a substance indeed triggers their AF "is an efficient use of these devices," Marcus said. Such N-of-1 exploration of possible triggers "might help free patients up to enjoy substances — caffeine or coffee is one example — that they otherwise might not, and may help actually reassure them that certain exposures — like certain exercises, which can also be beneficial — might actually not be harmful."

Marcus and the other authors on the report note — as he did at the AHA sessions — that the study has several limitations, such as the subjectivity of self-reported AF, dropouts from the trial that shrank the randomization arms, and a population that may not be very representative.

Some of the limitations may help explain why fewer AF episodes did not translate into improved quality of life, observed Biykem Bozkurt, MD, PhD, Baylor College of Medicine, Houston. With less trigger exposure, "one would assume that perhaps quality of life related to their atrial fibrillation symptoms would have improved," she told theheart.org | Medscape Cardiology.

Such a benefit might have emerged in a longer study with more patients, she proposed. Or perhaps the cohort experienced some AF not associated with symptoms or that caused cerebrovascular events. If so, "one may not be able to discern quality-of-life changes."

That AF episodes were identified subjectively suggests the potential for detection bias among those assigned to track their selected triggers, as Marcus and some observers have noted.

It follows that conscious avoidance of a potential AF trigger might well lead to a reduction in AF subjectively identified by symptoms, proposed David Conen, MD, MPH, Population Health Research Institute, McMaster University, Hamilton, Ontario, Canada. But perhaps no reduction would have been apparent had AF been objectively documented with the handheld ECG device, he told theheart.org | Medscape Cardiology.

"There were more subjective AF events than those objectively confirmed" using the handheld ECG monitor, he said, "suggesting that at least some of these so-called atrial fib events may have been just palpitations" or other symptoms unrelated to AF.

"In order to really study this question, we need to find out how strongly a specific trigger is associated to objective events," Conen said. "In this study, the only trigger that has really credible evidence is alcohol, and that's very consistent with clinical experience."

"If I were to redesign the study," he said, "I think the primary endpoint should be confirmed atrial fibrillation, because we would have to show first that the specific trigger actually reduced objective AF events before we then try to address the question whether reducing that trigger improves quality of life."

Unrepresentative Sample

The trial entered 446 overwhelmingly White and college-educated adults known to have symptomatic paroxysmal AF who were "interested in testing a presumed AF trigger they could readily introduce or withhold" and who owned a smartphone; the average age was 58 years, and 58% were men. The cohort was randomly assigned to the trigger-testing group or the control group, charged only with tracking their AF.

Of the total, 320, or about 72%, completed the study; those who did not were mostly from the trigger-testing arm, leaving 136 in that group vs 184 patients in the control group.

Potential triggers that participants selected for tracking included, foremost, caffeine, alcohol, reduced sleep, and exercise, followed by lying on the left side, dehydration, large meals, and cold food or drink, the report notes.

Patients in the control group used the smartphone app and handheld ECG monitor (KardiaMobile, AliveCor) to document the duration and severity of AF episodes daily and received data summary reports through the app weekly for 10 weeks. They then had the option to follow the trigger-testing protocol at least once.

Those in the trigger-testing group conducted their N-of-1 trials by exposing themselves to their chosen potential trigger during 3 separate weeks and avoiding the trigger during 3 other weeks, alternating each of the 6 weeks of trigger exposure or avoidance. They were instructed through the app to start the 6-week sequence with one or the other strategy randomly and to regularly track their AF.

At the end of 6 weeks, each participant in the trigger-testing group had the opportunity to review their data for any potential trigger–AF associations. They were then to use the next 4 weeks to enact lifestyle changes based on what they learned — as described in the report and on clinicaltrials.gov. They had the option of repeating the entire N-of-1 sequence at least one more time.

Participants in both the trigger-tracking and control arms were tested at baseline and at 10 weeks using the validated Atrial Fibrillation Effect on Quality-of-Life (AFEQT) questionnaire.

AFEQT scores didn't change significantly over the 10 weeks in either arm, nor were they significantly different in one arm compared to the other.

On the other hand, patients in the trigger-tracking arm reported significantly fewer daily AF episodes during the final 4-week period of lifestyle changes based on their N-of-1 trial results, compared to the monitoring-only control group's final 4 weeks.

The adjusted relative risk (RR) in the trigger-tracking arm was 0.60 (95% CI, 0.43 - 0.83; P < .001), the difference driven by patients who selected alcohol, dehydration, or exercise for their trigger, Marcus reported.

Only alcohol intake emerged consistently as a significant predictor of risk for self-reported AF episodes in a series of meta-analyses conducted using all of the individual N-of-1 trials that provided per-protocol data. The odds ratio  was 1.77 (95% CI, 1.20 - 2.69).

I-STOP-AFib explored an important subject "that has been understudied," Conen said. "The trial has some limitations that the authors address themselves, but hopefully it opens the path to future studies that can build upon this experience."

Marcus reports personal fees and equity interest from  InCarda Therapeutics; personal fees from Johnson & Johnson; and grants from Baylis Medical, Medtronic, the National Institutes of Health, the Patient-Centered Outcomes Research Institute, and the California Tobacco-Related Disease Research Program.  Bozkurt has disclosed consulting for Bayer and scPharmaceuticals and serving on a clinical-events committee for a trial supported by Abbott Pharmaceuticals and on a data and safety monitoring board for a trial supported by Liva Nova Pharmaceuticals. Conen has reported receiving speaker fees from Servier Canada.

American Heart Association (AHA) Scientific Sessions 2021. Presented November 14, 2021. LBS.04. Abstract.

JAMA Cardiol. Published November 14, 2021. Full text

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