The Prescribing Information For Eliquis Suggests Such Use Is Safe, But There Is Limited Clinical Study Data In Support

 

(Posted by Tom Lamb at DrugInjuryWatch.com)

 

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UPDATE:  Here are two new medical journal articles published in the November 7, 2016 edition of Clinical Journal of the American Society of Nephrology:

Use of Oral Anticoagulation in the Management of Atrial Fibrillation in Patients with ESRD: Pro

Use of Oral Anticoagulation in the Management of Atrial Fibrillation in Patients with ESRD: Con

(11/8/16)

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Pradaxa (dabigatran), Xarelto (rivaroxaban), Savaysa (edoxaban), and Eliquis (apixaban) are often referred to generally as novel oral anticoagulants (NOACs). This new class of blood-thinner drugs offers an alternative to Coumadin or warfarin for patients who do not want required frequent INR monitoring, strict dietary restrictions, and problematic drug-drug interactions.

In an August 2016 article, "Is Apixaban Safe and Effective for Patients on Hemodialysis?", Brandon Dyson, PharmD, BCPS, who is a clinical pharmacist at an academic medical center, puts some scrutiny on Eliquis, in particular:

NOACs are a good fit for many patients, but there are limitations. For instance, many NOACs have a higher bleeding risk than warfarin in certain settings, and except for dabigatran, no reversal agent is available. Another area where NOACs haven’t been able to replace warfarin is renal failure, specifically patients with end-stage renal disease (ESRD) on hemodialysis (HD).

[Eliquis (apixaban)] is the only NOAC approved for use with creatinine clearance <15 mL/min. In fact, according to its package insert, there isn’t even a dose adjustment.

[Eliquis (apixaban)] dosing in HD is a great illustration of why pharmacists learn to scrutinize clinical data. It’s why we need to sharpen our critical-thinking skills. [Footnote omitted.]

For that stated purpose, this clinical pharmacist looked at the Prescribing Information or package insert, as it is more commonly known, for Eliquis (accessed 11/1/16), with his focus on a specific part, "Patients with End-Stage Renal Disease on Dialysis", within the section "8.6 Renal Impairment":

Clinical efficacy and safety studies with ELIQUIS did not enroll patients with end-stage renal disease (ESRD) on dialysis. In patients with ESRD maintained on intermittent hemodialysis, administration of ELIQUIS at the usually recommended dose [see Dosage and Administration (2.1)] will result in concentrations of apixaban and pharmacodynamic activity similar to those observed in the ARISTOTLE study [see Clinical Pharmacology (12.3)]. It is not known whether these concentrations will lead to similar stroke reduction and bleeding risk in patients with ESRD on dialysis as was seen in ARISTOTLE.

 

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Returning to Brandon Dyson's analysis of this aspect of Eliquis safety in his above-referenced article:

So, the clinical trials for [Eliquis (apixaban)] didn’t include HD patients, but they’re able to recommend [Eliquis (apixaban)] use in HD patients with no dose adjustment. How?

You must dig deep to find the answer. The [Eliquis] package insert mentions a single-dose pharmacokinetic study in HD patients. If you dig a little further, you'll eventually find it, and you’ll find out it only involved 8 patients. You’ll also learn a bunch of other fun facts, like 27% of [Eliquis (apixaban)] is excreted unchanged in the urine, the drug’s AUC in HD patients is 36% higher than non-HD patients, and only 14% of [Eliquis (apixaban)] is removed during dialysis.

What happens if you give multiple doses? [Eliquis (apixaban)] dosing is 5 mg BID in most patients. Does it accumulate in HD? We don’t know; it hasn’t been studied.

All we currently have is data from a single-dose trial in 8 patients. And that’s the point I’m trying to make. [Eliquis (apixaban)] may very well be safe and effective in HD, but we don’t actually know. It might be safe, but not effective, or it might be effective, but not safe. It also may be neither.

That’s why we must be vigilant in data evaluation. We can’t blindly trust the FDA’s dosing recommendations. At a minimum, HD patients taking [Eliquis (apixaban)] need to be informed of the data limitations. They may be willing to sail uncharted waters, but they might not and decide it’s better to stick with warfarin. [Footnotes omitted.]

As for his mention of that eight (8) patient study, he referenced this medical journal article, "Pharmacokinetics, pharmacodynamics, and safety of apixaban in subjects with end-stage renal disease on hemodialysis.", published in the May 2016 print edition of The Journal of Clinical Pharmacology.

Of course, this clinical pharmacist's concern about — or skepticism of, perhaps — Eliquis use in the setting of hemodialysis piqued our interest.

All we were able to readily find on-point was this item, "Apixaban in Hemodialysis", on the ClinicalTrials.gov website, which provided us some rather limited information:

• This study has been completed.
• Sponsor: Jewish General Hospital
• First received: January 12, 2016
  Last updated: August 29, 2016
• This study aims to determine the effects of end-stage renal disease on the pharmacokinetics, pharmacodynamics, safety, and tolerability of [Eliquis (apixaban)]. This is a single-center open-label pharmacological study. [Eliquis (apixaban)] will be prescribed at the dose of 2.5 mg twice per day for nine days. The concentration of [Eliquis (apixaban)] will be measured with repetitive blood tests the first and the eighth day of administration (non-dialysis days). The same blood tests will be repeated before, during, and after dialysis on dialysis days. If the study shows inadequate or suboptimal efficacy with the [Eliquis (apixaban)] 2.5 mg dose, it will be repeated with the [Eliquis (apixaban)] 5 mg twice-daily dose.
• No Study Results Posted on ClinicalTrials.gov for this Study

So, it seems, there is still not much publicly available data about the safety of using Eliquis in the setting of hemodialysis. Yet, such use was apparently approved by the FDA.

If you know anything about the results of this particular Eliquis clinical study or some similar study, perhaps you can share it with us by submitting a Comment, below.

In the alternative, if you know of a patient on dialysis who suffered an adverse outcome while actively using Eliquis, we would be interested to hear about that situation.

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