CRAVE: No Spike in Atrial Arrhythmias Among Coffee Drinkers

Patrice Wendling

November 14, 2021

A novel trial using real-time monitoring found that drinking coffee did not increase atrial arrhythmias but was associated with more premature ventricular contractions.

There was no increase in premature atrial contractions (PACs) or supraventricular tachycardia (SVT) with coffee consumption, and, in fact, there was less SVT in per protocol analyses.

Coffee consumption was also linked to a "clinically meaningful increase in physical activity as well as a clinically meaningful reduction in sleep," co-principal investigator Gregory M. Marcus, MD, University of California, San Francisco, reported at the American Heart Association (AHA) Scientific Sessions 2021.

Although some professional society guidelines warn against caffeine consumption to avoid arrhythmias, he noted that the data have been mixed and that growing evidence suggests coffee consumption may actually lower the risk for arrhythmias, diabetes, and even mortality. The exact relationship has been hard to prove, however, as most coffee studies are observational and rely on self-report.

The Coffee and Real-time Atrial and Ventricular Ectopy (CRAVE) trial took advantage of digital health tools to examine the effect of caffeine consumption on cardiac ectopy burden in 100 healthy volunteers using an N-of-1 design. The primary outcomes were daily PAC and premature ventricular contraction (PVC) counts.

Participants consumed as much coffee as they wanted for 1 day and avoided all caffeine the next, alternating the assignment in 2-day blocks over 2 weeks. They used a smartphone app to receive daily coffee assignments and reminders and wore a continuous recording electrocardiography monitor (ZioPatch, iRhythm Technologies); a continuous glucose monitor (Dexcom); and Fitbit Flex 2, which recorded step counts and sleep duration.

At baseline, 21% of participants drank 6 to 7 cups of coffee per month, 29% drank 1 cup per day, 21% drank 2 to 3 cups per day, and 3% drank 4 to 5 cups per day. The U.S. Food and Drug Administration has cited 400 mg per day, or about 4 or 5 cups of coffee, as generally safe for healthy adults.

To assess adherence, participants were asked to press the button on the ZioPatch for every coffee drink and were queried daily regarding actual coffee consumption the previous day. Date-stamped receipts for coffee purchases were reimbursed, and smartphone geolocation was used to track coffee shop visits. The great majority of times, participants followed their assignment by all measures, Marcus said.

ITT and Per Protocol Analyses

ZioPatch data collected over a median of 13.3 days showed a daily median of 12.8 PACs, 7.5 PVCs, 1 nonsustained SVT, and 1 nonsustained ventricular tachycardia.

In intention-to-treat (ITT) analyses, there was no evidence of a relationship between coffee consumption and daily PAC counts (RR, 1.09; 95% CI, 0.98 - 1.20; P = .10).

In contrast, participants had an average of 54% more PVCs on days randomized to coffee by ITT (RR, 1.54; 95% CI, 1.19 - 2.00; P = .001) and, per protocol, those consuming more than 2 cups of coffee per day had a doubling of PVCs (RR, 2.20; 95% CI, 1.24 - 3.92; P = .007).

No relationship was observed with coffee consumption and SVT episodes in ITT analyses (RR, 0.84; 95% CI, 0.69 - 1.03; P = .10) but, per protocol, every additional coffee drink consumed in real time was associated with a 12% lower risk for an SVT episode (RR, 0.88; 95% CI, 0.79 - 0.99; P = .028).

No significant relationships were observed with VT episodes, which were admittedly rare, Marcus said.

In ITT analyses that adjusted for day of the week, participants took an average of 1058 more steps on days they drank coffee (95% CI, 441 - 1675 steps; P = .001) but slept 36 fewer minutes (95% CI, 22 - 50 minutes; P < .001).

Per protocol, every additional coffee drink was associated with 587 more steps per day (95% CI, 355 - 820 steps; P < .001) and 18 fewer minutes of sleep (95% CI, 13 - 23 minutes; P < .001).

No significant differences in glucose levels were observed. Genetic analyses revealed 2 significant interactions: fast coffee metabolizers had a heightened risk for PVCs and slow metabolizers experienced more sleep deprivation, Marcus said.

Typical Patients?

Dedicated discussant Sana Al-Khatib, MD, MHS, Duke University Medical Center, Durham, North Carolina, said CRAVE is a "well-conducted and informative trial" that very nicely and effectively used a digital health platform.

She pointed out, however, that the trial enrolled healthy volunteers who not only owned a smartphone but were able to interact with the study team using it. They also had an average age of 38 years, median body mass index of 24 kg/m2, and no prior arrhythmias or cardiovascular issues. "These are not representative of the average patient that we see in clinical practice."

"The other thing to keep in mind is that the primary outcome that they looked at, while relevant, is not adequate in my view to help us derive definitive conclusions about how coffee consumption affects clinically meaningful arrhythmias," Al-Khatib said. "Yes, PACs trigger atrial fibrillation, but they don't do so in every patient. And PVCs have been shown to be associated with increased mortality as well as worsened cardiovascular outcomes, but that's mostly in patients with structural heart disease."

She praised the investigators for including genetic data in their analysis. "Whether the results related to physical activity and sleep translate into any major effect on clinical outcomes deserves a study."

The overall findings need to be replicated by other groups, in other populations, and examining hard outcomes over longer follow-up, concluded Al-Khatib.

Speaking to | Medscape Cardiology, Marcus countered that the participants were "pretty run of the mill" coffee drinkers of all ages and that the study highlights the complexity of coffee consumption as well as providing unique data inferring causality regarding increasing physical activity.

"Because coffee is so commonly consumed, highlighting the actual effects is important and the hope is that understanding those true causal effects and minimizing confounding will help tailor recommendations regarding coffee consumption," he said. "For those concerned about atrial fibrillation, for example, these data suggest that avoiding coffee does not necessarily make sense to reduce the risk of atrial fibrillation. For those with ventricular arrhythmias, abstinence or minimizing coffee may be a worthwhile experiment."

Kalyanam Shivkumar, MD, PhD, director of the Cardiac Arrhythmia Center at the University of California, Los Angeles, told | Medscape Cardiology that CRAVE is an important and much-needed study that provides reassuring and objective data for a common clinical question.

"It fits in with the emerging consensus that, in itself, coffee is not problematic," he said. "And it provides a nice framework for what we'll be seeing in the future — more studies that use these types of long ECG recordings and interlinking that data with biological readouts."

Although it is too early to draw any conclusions regarding the genetic analyses, "future studies could use this is as a baseline to further explore what happens between fast and slow metabolizers. This is a very useful stepping stone to putting data in context for an individual patient."

Unless coffee consumption is excessive, such as over 5 cups per day in young people, all of the evidence points to coffee and caffeine being safe, Chip Lavie, MD, a frequent coffee researcher and medical director of cardiac rehabilitation and prevention at John Ochsner Heart and Vascular Institute, New Orleans, Louisiana, told | Medscape Cardiology.

"The benefits of coffee on physical activity/sleep seem to outweigh the risks as this current study suggests," he said. "This study also supports the safety with regards to atrial arrhythmias, and suggests that those with symptomatic PVCs could try reducing coffee to see if they feel better. In total, however, the benefits of one or several cups of coffee per day on cardiovascular disease outweigh the risks."

The study was funded by the University of California, San Francisco. Marcus reports research with the National Institutes of Health, the Patient-Centered Outcomes Research Institute, Tobacco-Related Disease Research Program, Medtronic, Eight Sleep, and Baylis; consulting for InCarda Therapeutics and Johnson & Johnson; and equity in InCarda Therapeutics as cofounder.

American Heart Association (AHA) Scientific Sessions 2021. Presented November 14, 2021.  LBS.03. Abstract

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