Large Quantities of Grapefruit Juice Prolong QT Interval

Batya Swift Yasgur, MA, LSW

May 17, 2019

Drinking large quantities of grapefruit juice may prolong the QT interval, especially in women and those who already have long QT syndrome (LQTS), new research suggests.

Investigators at Tel Aviv Sourasky Medical Center (TASMC) and Sackler Faculty of Medicine, Tel Aviv University, Israel, studied 10 patients with LQTS and 30 healthy volunteers. The volunteers received either 2 liters of grapefruit juice or 400 mg of oral moxifloxacin, which is known to affect QT interval, after which the interventions were crossed over. The LQTS patients received only grapefruit juice.

Electrocardiograms (ECG) of the LQTS patients showed significant QTc prolongation after drinking the juice, compared with the ECGs they underwent at baseline.

In healthy volunteers, grapefruit juice and moxifloxacin induced comparable QTc prolongation, with effects especially prominent in women.

"Our study shows that, in large doses, grapefruit juice prolongs the QT interval to a similar degree as moxifloxacin, an antibiotic with confirmed but low risk of torsades de pointes," corresponding author Sami Viskin, MD, director of cardiac hospitalization, TASMC, told theheart.org | Medscape Cardiology.

"Patients with LQTS should be informed that drinking grapefruit [juice] in large quantities may impose some risk, and when patients with LQTS present with arrhythmias, we should suggest that the medical history intake include questions about recently consumed food products," he said.

The study was presented at the Heart Rhythm Society 2019 Scientific Sessions and published online May 8 in HeartRhythm.

Pharmaceutical Protocol

"There are over 200 medications with reported QT-prolonging risk," lead author Ehud Chorin, MD, PhD, of the department of cardiology at TASMC, told theheart.org | Medscape Cardiology.

"The list of medications that may provoke a drug-induced LQTS is so extensive and diverse that it is not unreasonable to accept the idea that food products too might have QT-prolonging potential," he said.

"All of the medications that prolong the QT interval do so mainly by blocking a specific potassium channel on the myocardial cell membrane — the channel for the rapid component of the delayed rectifier potassium current, or 'IKr,' thus prolonging the ventricular repolarization," he explained.

The study was motivated by previous reports that some flavonoids contained in pink grapefruit block the IKr channel in vitro, he said.

The authors note that "thorough QT/QTc studies are routinely performed by pharmaceutical compan[ies] for developed drugs to get a better appreciation of their QT-prolonging potential."

These studies include, as a positive control, a medication with confirmed (albeit small) QT-prolonging properties — ie, 400 mg moxifloxacin, an antibiotic that reproducibly blocks IKr, leading to detectable QT prolongation.

The authors subjected grapefruit juice to the same rigorous protocol, using the criteria of the pharmaceutical industry.

The study included a control group of healthy volunteers and a group of patients with LQTS (n = 30 and n = 10, respectively). Volunteers were adults of normal weight, not taking medications, and with normal CCG. The patient group consisted of participants with type I, type II, and type III LQTS (n = 3, n = 5, and n = 2), respectively.

Patients taking beta-blockers continued their regimen, and implanted defibrillators were paced at 80 beats/minute.

Subjects were hospitalized for 2 days twice at a 7-day interval, with the study itself consisting of 4 days (2 at the beginning and end).

All ECGs were performed after 15 minutes of bed rest, with only minimal activity allowed between recordings, and all participants received the same diet throughout the study days.

Each day, 3 resting ECGs were performed 30 minutes apart starting at 8 AM; these were defined as the baseline ECGs for that day.

On day 1, ECGs were then performed every 60 minutes (defined as off-drug ECGs), and these were compared with the baseline recordings of that day to evaluate the spontaneous circadian variation of the QT/QTc.

On the second day, participants were randomly assigned to the interventional drug or fresh pink grapefruit juice administered in 3 divided doses after the completion of the baseline ECGs, with ECGs performed at regular intervals through the remainder of the day.

Subjects were discharged after 48 hours and then readmitted 7 days later for 2 additional days (designed as day 3 and day 4).

During day 3, the day 1 off-drug protocol was repeated. On day 4, the controls received the opposite intervention (grapefruit juice or moxifloxacin) of what they had received on day 2.

The patient group did not receive moxifloxacin and, since the first LQTS patient developed excessive QT prolongation after drinking grapefruit juice, the researches amended the protocol by reducing the amount of grapefruit juice administered, so that only the first 2 doses of juice were given to subsequent patients.

"Proarrhythmic Foods"

Neither moxifloxacin nor grapefruit juice significantly affected the heart rate of participants, and there were no adverse events. And in healthy volunteers, the circadian variation of QTc in the absence of drugs was small (P > .3 for all comparisons).

By contrast, the mean QTc increased significantly after exposure to moxifloxacin, with the moxifloxacin-induced QT prolongation peaking after 3 hours, with a maximal QTc prolongation of 20.4 msec (95% confidence interval [CI], 15.8 - 25.0).

The net QT increment from moxifloxacin was 17.5 msec (95% CI, 11.2 - 23.8; P < .001), with the difference from the corresponding off-drug measurement remaining statistically significant through hours 2 to 7 after moxifloxacin ingestion.

The QTc prolongation induced by grapefruit juice first became statistically significant 3 hours after the consumption of the first 1-liter and peaked at 4.5 hours, with maximal mean QTc prolongation of 13.8 msec (95% CI, 7.6 - 20.0) and a net QTc prolongation of 14.0 msec (95% CI, 6.2 - 21.7; P < .001).

The grapefruit-induced QT-prolongation lasted to the end of measurement period, with QTc values significantly longer than the corresponding off-drug measurements throughout hours 3 to 7 after the first dose.

Moxifloxacin had a stronger but not statistically significant effect on QTc prolongation, compared with grapefruit juice.

Patients with LQTS developed "marked" QT prolongation from grapefruit juice, which reached statistical significance as early as 2 hours after the consumption of 1-liter of grapefruit juice.

The effects peaked twice: once at 5.5 hours, with maximal mean QTc prolongation of 26.5 msec (95% CI, 14.9 - 38.2) and again 4 hours after the second dose, with maximal QTc prolongation of 29.7 (11.0 - 48.5).

Among patients with LQTS, the net QTc prolongation was 21.8 msec (95% CI, 3.4 - 35.3; P = .034), an effect that persisted until the end of the measurement period, with the difference from the respective off-drug values remaining statistically significant between 2 and 8 hours after the first grapefruit juice ingestion.

Among healthy volunteers, the individual maximal QTc prolongations for moxifloxacin and grapefruit juice at any time within 2 to 6 hours from drug administration were 28.6 ± 12.1 msec (range, 6.1 - 66.5) and 22.8 ± 11.0 msec (range, 7.1 - 58.7), respectively.

By contrast, the individual maximal QTc prolongation was 8.8 ± 9.6 msec (range, –8.0 to 35.3) during repeated off-drug measurements (P < .001).

For long-QT patients, the individual maximal QTc prolongation was 31.3 ± 17.8 msec (range, 8.3 - 57.7) at any time after grapefruit administration compared with only 10.1 ± 7.9 msec (range, –5.0 to 19.8) during multiple off-drug measurements (P = .004 for grapefruit juice vs off-drug values).

A mixed regression model showed that female gender and LQTS were independently associated with longer QT intervals.

Women had a stronger response to both moxifloxacin and grapefruit juice, compared with men (P < .05), while long QT patients had a stronger response to grapefruit juice compared with healthy volunteers (P < .001).

"The results of our study are straightforward," Chorin commented. "If grapefruit juice was a new drug, then the FDA would likely request the addition of a warning to include in its patient information leaflet."

"We have known proarrhythmic drugs for more than 44 years, and our manuscript suggests that we should be thinking about 'proarrhythmic food' as a real possibility," he added.

No Risk to the General Population

Commenting on the study for theheart.org | Medscape Cardiology, Peter Zimetbaum, MD, Richard A. and Susan F. Smith professor of cardiovascular medicine, Harvard Medical School, Boston, Massachusetts, called it a "very well conducted study with very balanced conclusions."

Zimetbaum, who is also associate chief and director of clinical cardiology at Beth Israel Deaconess Medical Center, Boston, said, "The authors note that the ingestion of grapefruit juice in large quantity — at least a liter — results in prolongation of the QT interval, [which is] an important observation in a rigorously conducted trial."

He added that the "caution to avoid ingestion of large quantities of grapefruit juice when taking medications which can prolong the QT interval — particularly antiarrhythmic drugs — makes a good deal of sense."

Viskin emphasized that their study "does not imply that daily consumption of grapefruit juice involves any measurement risk for the general population."

However, "a possible exception could be the consumption of 'health drinks' containing highly concentrated grapefruit products," he added.

The study was supported by an Israel Heart Society Research Grant. Chorin, Viskin, their coauthors, and Zimetbaum have disclosed no relevant financial relationships.

HeartRhythm. Published online May 8, 2019. Abstract

Heart Rhythm Society 2019 Scientific Sessions: Abstract S-PO03-191. Presented May 9, 2019.

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