Tag Archives: Eliquis

How Important Are Grapefruit (OR CBD Oil)-drug Interactions? David Bailey vs The Florida Dept. of Citrus

Previously, the skeptical cardiologist described a patient  with atrial fibrillation who was taking the blood thinner apixaban (Eliquis ) and developed a nose bleed after consuming a large amount of grapefruit (see here.)

In researching the whole subject of grapefruit-drug interactions I came across a fascinating intellectual battle between David Bailey, the researcher who first identified a significant grapefruit-drug interaction, and clinicians and researchers, some of whom are supported by the Florida Citrus Board, who feel this interaction is not significant.

What Does The Internet Tell Us?

It’s always interesting to see what patients doing a Google search will see on important medical topics. When I Googled  “grapefruit Eliquis interaction” I saw the following:

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The first item is an ad from the company that makes Eliquis which takes you to their patient-oriented Eliquis site and immediately presents you with important patient safety information. Nowhere on the site is the word grapefruit listed (as of July, 2018).

The second item is what Google calls a snippet and which they will present to you as what they think is the best answer to your Google search question. In this case the snippet  (and the first 4 hits) is lifted from Web MD an absolutely unreliable source of information (see my post on entitled Web Md:Purveyor of bad health information and snake oil) but one which Google (and thus millions of unsuspecting Googlers) relies on for answers to medical questions . Web MD advises you to avoid grapefruit if you’re taking eliquis.

Close inspection of the WebMD article proffering this advice reveals the sole reference that actually bears on this topic: (Bailey et al , 2012 , CMAJ).

The main author of this paper (which has  the oddly phrased title Grapefruit–medication interactions: Forbidden fruit or avoidable consequences? ) is David Bailey.

David Bailey: Rapid Runner and Grapefruit Alarmist

David Bailey may be  better  known as the first Canadian to run a mile in under 4 minutes. His Wikipedia entry spends equal time on his running career and on his major claim to fame: grapefruit drug interactions (GDI).

Bailey serendipitously discovered that grapefruit increased levels of the antihypertensive drug felodipine in his own body in 1987,  information which was pretty much ignored until he published a research paper in the Lancet in 1991 showing a doubling of felodipine levels in 6 volunteers who consumed grapefruit.

Since then studies have shown that grapefruit juice  acts by reducing presystemic felodipine metabolism through selective post-translational down regulation of cytochrome P450 3A4 (CYP3A4) expression in the intestinal wall.

Bailey has taken the grapefruit (and Seville orange) ball and run with it. His publications emphasize the broad scope and potential dangers of multiple grapefruit-drug interactions.  A 2012 Bailey paper  lists 85 drugs with the potential to interact with grapefruit juice including, you guessed it, apixaban.

Despite these potential interactions the actual number of clinically significant interactions or harm reported is minuscule. This has not deterred Bailey from emphasizing the importance of the interaction he discovered.

He is  quoted in a 2012 NY Times article as saying:

“The bottom line is that even if the frequency is low, the consequences can be dire,” he said. “Why do we have to have a body count before we make changes?”

“For 43 of the 85 drugs now on the list, consumption with grapefruit can be life-threatening, “

Articles, like the NY Times article typically  buy into Bailey’s fear-mongering and spend multiple paragraphs describing a single case report suggesting that ingestion of grapefruit juice was responsible for a dangerous  interaction but such cases are rare and strong evidence that grapefruit juice was responsible is not present.

What Can We Learn From The Florida Department of Citrus?

In fact, in a letter to the editor in response to Bailey’s 2012 review, two researchers point out that their is little solid evidence to suggest that the grapefruit-drug interactions are important

We know of no validated evidence that coadministration of grapefruit juice with a drug has caused a dangerous interaction, resulting in serious adverse effects or actual harm to a patient’s health. We point readers to 2 extensive review articles on grapefruit juice–drug interactions that have appeared in peer-reviewed medical literature.2,3 These articles provide a review of primary research literature, a compilation of the extent of interactions with specific drugs, and an evaluation of their clinical importance; however, neither of these publications is cited in the CMAJ article.

Whereas David Bailey has a bias to promote and exaggerate an interaction that is his claim to scientific fame most of the research and reviews that counter his claims come from researchers who are likely heavily biased to minimize the importance of the interaction: they are funded by the Florida Department of Citrus.

Are We Missing Important Grapefruit Medication Interactions?

David Bailey would like  us to believe that the GFDI he identified in 1998 is hugely important. If only doctors would spend more time investigating the grapefruit consumption of their patients we would realize this.  He writes

But how big a problem are such interactions? Unless health care professionals are aware of the possibility that the adverse event they are seeing might have an origin in the recent addition of grapefruit to the patient’s diet, it is very unlikely that they will investigate it. In addition, the patient may not volunteer this information. Thus, we contend that there remains a lack of knowledge about this interaction in the general health care community. Consequently, current data are not available to provide an absolute or even approximate number representing the true incidence of grapefruit–drug interactions in routine practiceThe chemicals in grapefruit involved in this interaction are the furanocoumarins.7

Bailey, goes on to warn us that all forms of grapefruit consumption can lead to dangerous interactions and other citrus fruits are to be feared as well

Because these chemicals are innate to grapefruit, all forms of the fruit (freshly squeezed juice, frozen concentrate and whole fruit) have the potential to reduce the activity of CYP3A4. One whole grapefruit or 200 mL of grapefruit juice is sufficient to cause clinically relevant increased systemic drug concentration and subsequent adverse effects.11,12 Seville oranges, (often used in marmalades), limes and pomelos also produce this interaction.1315 Varieties of sweet orange, such as navel or valencia, do not contain furanocoumarins and do not produce this interaction.2

You can follow his references but they are not to patients who were harmed by grapefruit-drug interactions. Indeed, I am unaware of any of my patients reporting such harm until my patient with the nose bleed. I tend to agree with this unbiased editorial from BMJ in 2013

In our experience, and in that of our experienced colleagues, we have yet to come across clinically meaningful interactions of drugs and GFJ. This is despite our day to day experience of managing patients on statins, calcium channel antagonists, anti-platelet agents and anti-arrhythmics, which covers over 10,000 patients in the last 10 years alone. Likewise, there is little formal evidence of an impact, even from large scale clinical trials, with adjudicated and well documented endpoints.

After considerable research and communication with Pfizer, the maker of Eliquis, I ended up agreeing with Pfizer’s conclusion that the grapefruit-Eliquis interaction was unlikely to be significant:

When consumed in usual dietary volumes, grapefruit juice is considered a moderate inhibitor of CYP3A4. Therefore a dose adjustment of apixaban is not expected to be required.

CBD Oil, Grapefruit And Drug Interactions

I was reminded of the grapefruit-drug interaction in the last few weeks as several of my patients have started using CBD oil for various problems and have asked if it is safe to use with their cardiac medications.

I haven’t fully researched the CBD oil-drug interaction but the top Google search (“grapefruit and CBD oil”) result (from CBD school)  states the following:

CBD interacts with other medications in your body in the same way as grapefruit, only even stronger.

However, the site that CBD school references (Project CBD) is not that definitive about grapefruit-drug interactions being a guide to CBD-grapefruit interactions.

And a recent scholarly article on the topic (see here) concludes

The drug-drug interactions between cannabinoids and various drugs at the CYP level are reported, but their clinical relevance remains unclear.

Which sounds very similar to where we are at with grapefruit-drug interactions in general.


I had my patient perform an experiment to see if the grapefruit actually caused her nose bleed. She repeated her consumption of large amounts of grapefruit and had no nosebleed this time.

Nonepistaxisly Yours,

-ACP

Is It Safe To Consume Grapefruit If You Take The Blood Thinner Apixiban (Eliquis)?

A patient of mine with atrial fibrillation taking the blood thinner eliquis told me that she had eaten grapefruit for two days in a row and then developed a nose bleed. She had heard of the interaction between grapefruit and certain medications and wondered if this had caused her nose bleed.

I was unaware of any eliquis/grapefruit interaction but thought this was a remarkably astute observation and question and set about to research it properly.

Among other things, I discovered that some researchers believe the grapefruit-drug interaction to be a widespread , underreported and  highly significant problem while others feel it is overblown and a rare cause of clinically important side effects.

For those, who prefer not to delves into the gory details I give you the crux of what BMS/Pfizer, the makers of apixiban (Eliquis) told me and with which I agree:

When consumed in usual dietary volumes, grapefruit juice is considered a moderate inhibitor of CYP3A4. Therefore a dose adjustment of apixaban is not expected to be required.

In other words, although not formally studied, there is no evidence that apixiban levels are increased by moderate grapefruit juice ingestion to a degree that would cause significant bleeding complications.

Although multiple sites on the internet (including the unreliable Web MD) will tell you of a potentially dangerous interaction between grapefruit and apixiban this theoretical interaction has not proven clinically significant.

Interactively Yours,

-ACP

Below is the full text of the letter BMS sent me

Bristol-Myers Squibb and/or Pfizer have not conducted any studies evaluating the concomitant use of apixaban and grapefruit juice. The decision to prescribe apixaban in patients who are concomitantly taking grapefruit juice is a clinical decision for the treating physician based on the individual’s circumstances and inaccordance with the full prescribing information for apixaban.

While in vitro data indicates grapefruit juice can inhibit both cytochrome P450 (CYP) 3A4 and P-glycoprotein (P-gp), clinical evidence suggests that grapefruit juice mediated interactions would be primarily due to the inhibition of CYP3A4 and the contribution of P-gp inhibition may be limited.1, 2 When consumed in usual dietary volumes, grapefruit juice is considered a moderate inhibitor of CYP3A4.1 Therefore a dose adjustment of apixaban is not expected to be required.

Apixaban is eliminated from the body through multiple pathways, with approximately 25% of the administered dose recovered as metabolites. The main metabolic pathway for apixaban is through CYP3A4/5, with minor contributions from other CYP isoenzymes. Apixaban is also a substrate of transport proteins P-gp and breast cancer resistance protein.3

  1. [1]  Hanley MJ, Cancalon P, Widmer WW,et al. The effect of grapefruit juice on drug disposition. Expert Opin Drug Metab Toxicol. 2011; 7(3):267-286.
  2. [2]  Farkas DG and Greenblatt DJ. Influence of fruit juices on drug disposition: discrepancies between in vitro and clinical studies. Expert Opin Drug Metab Toxicol. 2008;4(4):381-393.
  3. [3]  Eliquis® (apixaban) Package Insert. Bristol-Myers Squibb Company, Princeton, NJ and Pfizer Inc, New York, NY

Why Does The TV Tell Me Xarelto is a BAD DRUG?

One of my patients called the office today concerned about a medication she was taking because she was “seeing about 4-5 commercials a day about how bad Xarelto is”.

She is the latest of many of my patients who have been inundated with ads like these which state in very strident tones that a drug is bad and that if “you or a loved one has had a serious bleeding problem” contact 1-800-BAD DRUG and see if you are eligible for compensation.

These drugs are not bad and the only reason these advertisements are being played is that tort lawyers sense an opportunity to make money.

To understand why they are flooding the TV market now I will have to give you some background on atrial fibrillation , stroke and the drugs available to reduce stroke risk.

Preventing Stroke Associated With Atrial Fibrillation

Patients with atrial fibrillation are at increased risk of stroke and since the 1950s the only drug available for doctors to reduce clot formation in the heart and susbsequent strokes was warfarin (brand name Coumadin). Warfarin is only effective and safe within a narrow window and its effects are strongly influenced by Vitamin K in the diet and most medications. Thus, frequent blood testing is needed, and close monitoring of diet and changes in medications. Even with this close monitoring, serious and sometimes fatal bleeding occurs frequently with warfarin.

Novel Anticoagulants

In recent years, three new drugs for reducing strokes in patients with atrial fibrillation which are much less influenced by diet and medications have gained approval from the FDA. These are generally referred to as “novel anticoagulants” reflecting their newness, different effects from warfarin or aspirin, and their blood thinning properties.  The first  (brand name Pradaxa) was released to much excitement and fanfare in October, 2010.  The press release for this approval read as follows:

PRADAXA, an oral direct thrombin inhibitor2 that was discovered and developed by Boehringer Ingelheim, is the first new oral anticoagulant approved in the U.S. in more than 50 years. As demonstrated in the RE-LY® trial, PRADAXA 150mg taken twice daily has been shown to significantly reduce stroke and systemic embolism by 35 percent beyond the reduction achieved with warfarin, the current standard of care for patients with non-valvular atrial fibrillation. PRADAXA 150mg taken twice daily significantly reduced both ischemic and hemorrhagic strokes compared to warfarin

Differences Between Warfarin and the Novel Anticoagulants

What was very clear from the study with Pradaxa  and stated very clearly in all publications and patient and doctor  information sources was that just like warfarin, patients could have severe bleeding complications, sometimes fatal. Overall serious bleeding complications were about the same (the rate of major bleeding in patients Pradaxa  in the RE-LY trial was 3.1% versus 3.4% in the warfarin group) but Pradaxa had about 50% more bleeding from the gastrointestinal tract and warfarin about 50% more bleeding into the brain.

Another big difference between the novel anticoagulants and warfarin is that we have antidotes (Vitamin K, fresh frozen plasma) that can reverse the anticoagulation state rapidly for warfarin but none for the newer drugs. This information also was made very clear to all doctors prescribing the medications in the package insert and educational talks. Despite this, in the major trials comparing these newer agents to warfarin, the newer agents were as safe or safer than warfarin.

The Pradaxa Bad Drug Ads

Beginning about a  year after Pradaxa was released advertisements paid for by law firms seeking “victims” of Pradaxa  identical to the ones we are now seeing for Xarelto began to appear.

The Pradaxa ads went away in mid 2014 when these lawsuits were settled and almost immediately the lawyers began paying for Xarelto ads. Xarelto was the second “novel anticoagulant) to be approved by the FDA and, similar to Pradaxa, was proven to as effective as warfarin in preventing strokes with a similar rate of serious bleeding complications.

As the Wall Street Journal noted (with the catchy title “The Clot Thickens” and opening line “Is a blood thinner causing lawyers to smell blood?”)

“Spending (on Xarelto ads)  jumped to $1.2 million in July from just $8,000 in June, according to The Silverstein Group Mass Tort Ad Watch, which noted the number of ads that ran in July exceeded 1,800. …

The spending increased shortly after Boehringer Ingelheim, which sells a rival blood thinner called Pradaxa, last May agreed to pay $650 million to settle about 4,000 lawsuits over claims the drug caused serious bleeding episodes. The settlement likely emboldened attorneys to turn their sights toward Xarelto which, like Pradaxa, is one of a relatively new batch of blood thinners.”

The third drug to be approved for preventing strokes in atrial fibrillation was Eliquis. Data from the large, randomized study comparing it to warfarin suggest that it is more effective at preventing stroke than warfarin and significantly less likely to have bleeding complications. However, I predict that within the year (especially if the Xarelto lawsuits also are settled by its manufacturer) we will start to see lots of TV ads telling us that Eliquis is a BAD DRUG.

It’s important to remember that all drugs have benefits and side effects. Seemingly harmless antibiotics can increase your risk of dying suddenly (see here), rupturing your achilles tendon or developing a life-threatening colitis.

Xarelto is not a BAD DRUG. When prescribed to appropriate patients with atrial fibrillation with  appropriate precautions it prevents strokes which are potentially life-threatening or disabling. All blood thinners are two-edged swords: they stop good clots and bad clots.

Ignore The Ads

Patients are better off ignoring both positive, direct to consumer, advertisements, promoting these newer anticoagulants and negative, greedy-lawyer sponsored advertisements, soliciting “victims”.

Hopefully when your doctor discusses the choices of blood thinners with you he will present to you a balanced discussion of the pros and cons both of whether or not to take  a blood thinner and whether to take the old standby warfarin or one of the newer agents. An interactive discussion should follow in which your particular issues and concerns factor into the final decision.