Grapefruit Juice Prolongs QT Interval, but How Much Does It Matter?

SAN FRANCISCO, CA—Consuming a large quantity of grapefruit juice has effects on the QT interval in healthy adults similar to those seen with moxifloxacin, an antibiotic with known QT-prolonging effects, and there is an even greater impact seen in patients with long QT syndrome, new data show.

But there’s no reason to panic, since the observed changes were relatively small, senior author Sami Viskin, MD (Tel Aviv University, Israel), told TCTMD.

“The first message is for patients taking QT-prolonging medications. They already know they should avoid grapefruit juice for a different reason, that it prevents the metabolism of the drug. But now there is a second reason: that on top of the QT-prolonging drug they will get additional QT prolongation,” Viskin said.

Patients with congenital long QT syndrome “should avoid at least large quantities of grapefruit,” he said.

And for people in the general population, “I think the risk is too small to really give any message to avoid drinking grapefruit juice,” Viskin said. One note of caution, however, is that there are certain health drinks that contain very high concentrations of grapefruit juice. “We should take a look at those drinks [and] what they do, because it is possible that a very high concentration of grapefruit juice in health drinks could be dangerous even for healthy individuals if they use them on a regular basis. I don’t know, but it could be.”

The findings were presented by lead author Ehud Chorin, MD, PhD (Tel Aviv University), at the Heart Rhythm Society (HRS) 2019 Scientific Sessions here and published simultaneously online in Heart Rhythm.

More than 200 medications—including some antiarrhythmics, antibiotics, antihistamines, and antipsychotics—are known to prolong the QT interval, mostly through a mechanism that involves blocking the I_Kr potassium channel on the myocardial cell membrane. Patients with congenital long QT syndrome are commonly told to avoid these drugs.

But certain compounds in food could have similar effects. Prior research has shown that grapefruit contains flavonoids, which also block the I_Kr potassium channel, and that drinking 1 liter of grapefruit juice induces a small QT prolongation in healthy people.

“This is important,” the authors write in their paper, “because drugs causing minor QT prolongation in healthy volunteers may provoke significant QT prolongation when administered to large, unselected patient populations with comorbidities, and may rarely provoke torsade de pointes in susceptible individuals.”

To better characterize the effect of drinking grapefruit juice on the QT interval, Chorin, Viskin, and colleagues performed a randomized, crossover study using the strict methodology employed by pharmaceutical companies to evaluate the QT-prolonging potential of new drugs. The study included 30 healthy adult volunteers and 10 patients with congenital long QT syndrome, who were hospitalized for 2 days on two separate occasions separated by a week.

In a randomized fashion, healthy participants were given grapefruit juice during one hospitalization and a single, oral, 400-mg dose of moxifloxacin during the other. They drank 2 liters of grapefruit juice total—1 liter after baseline ECGs and then two half-liter doses 4 and 6 hours later.

Patients with long QT syndrome received only grapefruit juice for ethical reasons. The first patient with long QT syndrome to consume 2 liters of juice had excessive QT prolongation, so the remaining patients drank only 1.5 liters.

The investigators found that drinking grapefruit juice did indeed lengthen the QT interval. In the healthy volunteers, the absolute net prolongation of the rate-corrected QT interval was 14.0 msec, similar to what was seen with exposure to moxifloxacin (17.5 msec). The effects of grapefruit juice were particularly pronounced in women.

In addition, the QT-prolonging effects of grapefruit juice—despite the lower exposure dose—were even greater in patients with long QT syndrome, with an absolute net prolongation of 21.8 msec. Grapefruit juice resulted in a marked QT prolongation (40 msec or greater) more frequently in patients with long QT syndrome than in the healthy volunteers.

Commenting for TCTMD, HRS spokesperson Fred Kusumoto, MD (Mayo Clinic, Jacksonville, FL), said that the study is another illustration of the fact that everyday exposures could have potentially big implications, noting that amiodarone and other antiarrhythmic drugs started out as herbs.

Is a blanket warning appropriate? No, I think that that would cause a lot of issues with regards to undue concern. Fred Kusumoto

It’s been known that grapefruit juice can affect the bioavailability of certain drugs, and the additional effects on the QT interval observed here are important for overall awareness, Kusumoto said.

But he stopped short of advocating for the strengthening of existing warnings or the placement of new warnings on drug labels based on these findings, pointing out that participants had to drink a large quantity of grapefruit juice to induce these relatively small effects that would not be associated with harm in most cases.

“Is a blanket warning appropriate? No, I think that that would cause a lot of issues with regards to undue concern,” commented Kusumoto. But for cardiologists, specialists who treat long QT syndrome, and arrhythmia clinics, he added, “Should they have this as something that they should talk about? Absolutely.”

He said he wouldn’t bring it up with all of his patients but might in a patient with long QT syndrome who has a QT interval of 480 or 490 msec—in whom drinking grapefruit juice could push that number up over 500 msec.

Viskin said the information from this study could be helpful when evaluating patients who present with arrhythmias and QT prolongation. “Just as physicians are used to inquiring about the medications they took in recent days, they should inquire about the foods that they ate in recent days [because] maybe that played a function in provoking the arrhythmias,” he said.