New Oral Anticoagulants Can Require Careful Dosing Too

[EngMac]

medscape.com/viewarticle/87...

NEW YORK (Reuters Health) - While non-vitamin K antagonist oral anticoagulants (NOACs) offer safe and effective prevention of stroke or systemic embolism in patients with atrial fibrillation (AF), and simpler administration than warfarin, they too can require careful dose adjustment, U.S. researchers say.

"While these new drugs are relatively easier to manage than warfarin (coumadin), there are still dose adjustments that need to be made for certain patients," co-author Dr. Benjamin A. Steinberg of the University of Utah in Salt Lake City told Reuters Health in an email. "And while the dosing of NOACs will change less frequently than with warfarin, it is important to periodically assess a patient's dose, as factors like renal function and concomitant medications can change."

"Our data suggest most patients are receiving the appropriate dose for stroke prevention in atrial fibrillation," he added. "However, a minority was not, and the use of off-label dosing was associated with worse clinical outcomes."

Off-label NOAC doses were found in about one in eight patients in U.S. community practice, the researchers report.

Further, patients who received higher-than-recommended doses had significantly greater all-cause mortality (adjusted hazard ratio: 1.91). Those receiving lower-than-recommended doses had significantly more cardiovascular hospitalizations (aHR: 1.26) than those prescribed the recommended doses.

In an editorial, Dr. Daniel M. Witt and Dr. Alisyn L. Hansen of the University of Utah College of Pharmacy wrote, "Unfortunately, these results likely underestimate the true magnitude of non-approved NOAC doses in real-world clinical practice and represent an important warning to clinicians prescribing NOACs."

"Oral anticoagulants are high-risk medications," they cautioned, noting that "precise dosing decisions" are needed "regardless of whether warfarin or NOACs are prescribed."

For the study, released online on December 12 by the Journal of the American College of Cardiology, the researchers used data from the ORBIT-AF II registry of patients with AF, which is sponsored by Janssen Scientific Affairs LLC.

The study group included 5,738 patients: 425 treated with dabigatran (7.4%), 3,078 with rivaroxaban (53.6%), and 2,235 with apixaban (39%).

Compared to those whose doses were consistent with the specific NOAC's FDA-approved package insert, patients who received under- or over-doses of NOACs were significantly older (median 79 and 80 years of age vs. 70 years of age, respectively), more likely to be female, and more likely to have high ORBIT bleeding scores.

The researchers noted the difficulty in gauging the intentions of physicians who prescribed higher- or lower-than-recommended NOAC doses. Still, they suggest, "the underlying risks of the cohort suggest potential intentional deviation from approved doses."

They noted, for example, that underdosed patients had significantly higher ORBIT bleeding scores than those given recommended doses. "Physicians may be tailoring the doses of these medications to the specific patient's underlying risk," the report concluded.

[MarkS]

Very interesting. The main problem for me with NOACs is that they can't be tested like warfarin, and their effect does vary from person to person.

[Pur123 in reply to MarkS]

I found documents from a lawsuit against Xarelto, two MDs and a Pharm testifying that the FDA in fact did tell Xarelto that the once daily 20mg dosage would be better halved and given 2x daily. Also that some testing should be done as there were differences in absorption putting some people at risk for hemorrhagic stroke and others undercoagulated. That testimony is here: fjdefile.phila.gov/efs/temp... here: fjdefile.phila.gov/efs/temp...

and here:fjdefile.phila.gov/efs/temp...

Well unfortunately these urls become removed/invalid within minutes of saving them. And when you do find them each time, they have a different url containing the word 'temp.'

The only way to find these testimonies from three MDs now is search for Phillip Cuculich Xarelto fjdefile.phila.gov (that Exhibit testimony is LL) Also Burt Gerstman Xarelto fjdefile.phila.gov and Henry Bussey Xarelto fjdefile.phila.gov I hope you can find them and save/ print as a pdf for review. Very important information for everyone.

[Hidden]

Thank you for posting this. I found this very interesting as one who is considering switching to a NOAC

[CDreamer]

Maybe it was just me but I found that report very vague. I got the impression that this information pertained to US 'off label, community practice' - what does this mean please?

The figures quoted as higher risk of bleed were in the older age group, which is well known to have to need a different dose as there is a much higher risk of bleeds due to fragile blood vessels from aging. It also indicates that the group included people who were not monitored for renal function? I think everyone in the U.K. is monitored - I know I have monthly tests but for drugs other than anticoagulants - but I used to have 6 monthly bloods for NOACs.

Whilst it may be of some interest and I believe there are some moves for testing of NOACs - I am somewhat cynical of the reasoning for this - mainly more testing = more money and my understanding is the test would be more complicated and more costly. Somehow I don't think this is going to happen in the UK without significant gold standard research indicating the necessity.

I wonder who sponsored the research? Maybe will do a little digging.........

[rosyG]

This just seems to be saying that if guidelines on dosage are not followed, outcomes are bad for the patient- true about any drug I think- and the change in dosage is suspected to be because of other factors- age-kidney function etc- which would affect the health of the patient regardless.

I have great respect for Mark's way of using Warfarin, having heard him explain this, but am not sure how you estimate that NOACS have a different effect on individuals Mark? Of course, if renal function or liver function is poor, any drug will affect patients differently - hence dosage guidelines- but surely the very large studies on NOACS can give us the effect they have - because of the numbers re reduction in ICH and figures on strokes??

[BobD Volunteer]

This is surely a prime case of stating the bleeding obvious! I am not aware of any UK doctors doing their own thing with doses so I agree with CDreamer here. Bad practice should not be tolerated.

[Pacific]

Yes, it's a bit confusing. It's clearly a US website, yet in the US they do not describe AF as Atrial Fibrillation, but as afib, (there must be a pun in here somewhere!).

Also the NOAC's have a shorter life, and also they have been available in the US for many years now. Off - label means not prescribed for that purpose. For example, Lyrica is prescribed as an anti seizure drug, but it can be used off - label for neuropathic pain relief.

It reads as though someone has edited it, perhaps to make it understandable in British lingo, but forgetting to omit the Yankee Doodle phrases.

Still, it's always interesting to read different opinions.