'Well-Managed Warfarin' Good Enough in Atrial Fib: Analysis

'Well-Managed Warfarin' Good Enough in Atrial Fib: Analysis

Marlene BuskoApril 22, 2016

SUNDSVALL, SWEDEN — Low rates of intracranial bleeding and other complications and low all-cause mortality were observed over 9 years of follow-up in a large registry study from Sweden looking at patients with atrial fibrillation (AF) who overall had well-managed anticoagulation with warfarin[1]. It also pointed to some risk factors for such complications, including renal failure and concomitant aspirin use.

"Well-managed warfarin therapy is associated with a low risk of complications and is still a valid alternative for prophylaxis of AF-associated stroke. Therapy should be closely monitored for patients with renal failure, concomitant aspirin use, and poor INR control," Dr Fredrik Björck (Umeå University, Sundsvall, Sweden) and colleagues summarize in a report published April 20 in JAMA Cardiology.

Historically, observes an accompanying editorial[2], "among patients with AF, Sweden has some of the best INR [international normalized ratio] control in the world," so these results may not be generalizable. Moreover, the study does not provide insight into which patients with well-managed warfarin therapy would have better outcomes with the novel oral anticoagulants (NOACs) than with warfarin.

"Features related to good INR control, such as adherence, lack of interruptions, and better health care, might also contribute to good outcomes with NOACs," according to editorialists Drs John H Alexander and Laine E Thomas (Duke Clinical Research Institute, Durham, NC).

In Sweden, Björck told heartwire from Medscape, "warfarin is still a valid option, along with NOACs," for patients with AF. The analysis was not designed to compare outcomes with a NOAC versus well-controlled warfarin therapy, but he agreed with the idea that adherence and other factors related to good INR control "might enhance outcomes for NOACs as well."

Finding the Right Fit?

Of note, the mean time in therapeutic range (TTR) in the registry analysis was 68.6%. That compares to 53.7% in the United States in a 2014 report[2], according to Dr Xiaoxi Yao (Mayo Clinic, Rochester, MN) speaking with heartwire .

Yao, who is not associated with the current study, agreed that factors that promoted good INR control in the Swedish cohort could well do the same for NOACs. And warfarin has well-recognized downsides, she noted. "Warfarin requires regular INR testing, dose adjustments, and has numerous interactions with food and other drugs and adherence is notoriously poor," she said.

"This study underscores the importance of close monitoring patients with suboptimal warfarin control and those on concomitant treatment of antiplatelet or aspirin," according to Yao.

"It has long been known that European national health systems do a better job with warfarin than we do," said Dr Joseph Alpert (University of Arizona College of Medicine, Tucson), also not involved in the Swedish registry analysis. A warfarin TTR of 55% is considered good in the United States, he said in an interview.

"In a national healthcare system, it is likely that patients get better follow-up than in a patchwork quilt system like in the US," he said. Still, "Our patients who do very well chronically on warfarin and are stable can remain on warfarin here as in Europe. Those whose INRs are unstable here in the US should be considered for one of the new anticoagulants."

Real-Life Data, Good Safety Profile

To investigate outcomes of well-controlled warfarin therapy, the authors identified 40,449 patients receiving warfarin for nonvalvular AF and were enrolled in Swedish registries, notably the National Registry for Auricular Fibrillation and Anticoagulation (AURICULA), from 2006 to 2011, and had follow-up data until 2015.

More than half of the patients (60%) were men. Overall, the cohort had a mean age of 72 years and mean CHADS2 score of 2.1, similar to that in the NOAC trials, according to the authors.

The annual incidence of intracranial bleeding was 0.44%, which was lower than in the warfarin control groups in the pivotal NOAC trials (0.70%–0.85%) and close to the rate with NOACs (about 0.3%), according to the authors.

Similarly, the annual incidence of all-cause mortality was 2.2%, which is lower than in the warfarin- and NOAC-treated patients in the NOAC trials (3.9%–4.9% and 3.5%–4.5%, respectively).

Patients who received concomitant aspirin had higher annual rates of major bleeding (3.07%) and thromboembolism (4.90%). Patients with renal failure had a 2.25-fold higher risk for intracranial bleeding.

Patients who had an individual TTR below 70% also had higher annual rates of major bleeding (3.81%) and thromboembolism (4.41%), as did patients with high INR variability (3.04% and 3.48%, respectively).

Monitoring May Be "One of the Keys"

"The goal is to find an anticoagulant that fits for [a particular] patient," said Björck. "The need for monitoring in warfarin might be one of the keys in achieving high long-term adherence to treatment, which is crucial for outcome in AF and anticoagulants," he noted. "The question is, how to achieve high adherence with NOACs?"

Where warfarin monitoring is expected to be difficult (for example, a patient may have sporadic contact with the healthcare system or may have communication difficulties due to aphasia), a NOAC may be the drug of first choice, he said.

On the other hand, "our study shows that for patients achieving TTR over 70%, and not being treated with additional acetylsalicylic acid, the probability of good outcome on further warfarin treatment is likely."

Björck has disclosed no relevant financial relationships; disclosures for the other authors are listed with the article. Alexander reports institutional research grants from Boehringer Ingelheim, Bristol-Myers Squibb, CSL Behring, Pfizer, Sanofi, Regado Biosciences, Tenax, and Vivus and consulting fees/honoraria from Bristol-Myers Squibb, CSL Behring, Daiichi Sankyo, GlaxoSmithKline, Janssen, Pfizer, Portola, Sohmalution, and Xoma. Thomas reports institutional research grants from Bristol-Myers Squibb, Pfizer, and Janssen Scientific Affairs. Alpert is the editor in chief of the American Journal of Medicine and reports serving on the data safety and monitoring board for the ROCKET-AF and PIONEER studies, two trials involving rivaroxaban. Yao has disclosed no relevant financial relationships.

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Björck F, Renlund H, Lip GYH, et al. Outcomes in a warfarin-treated population with atrial fibrillation. JAMA Cardiol 2016; DOI:10.1001/jamacardio.2016.0199. Full text

Alexander JH, Thomas LE. Using data to guide anticoagulation in patients with atrial fibrillation: does the analysis fit the question? JAMA Cardiol 2016; DOI:10.1001/jamacardio.2016.0198. Full text

Dlott JS, George RA, Huang X, et al. National assessment of warfarin anticoagulation therapy for stroke prevention in atrial fibrillation. Circulation 2014; 129:1407-1414. Full text


Heartwire from Medscape © 2016 Medscape, LLC

Cite this article: 'Well-Managed Warfarin' Good Enough in Atrial Fib: Analysis. Medscape. Apr 22, 2016.

7 Replies

  • Thanks Nepti.

    I think that this study simply confirms what we have all know for some time, that well managed warfarin is probably the best option for most people.

    However it does need the emphasis on well managed, and as mentioned above for many people only manage to get just over 50% of the time in therapeutic range.

    Honestly for myself if I could stay in range and also could self test and self adjust (which my doctor forbids, I'm far too stupid of course, this the same doctor who had never heard of Apixiban let alone Dabigatran) I would be happier on tried and tested warfarin than I am on Rivaroxaban. At least we have a long tried and tested understanding of the long term effects.

    Be well


  • I must be quite lucky then as I just did some sums and in the last 7 years I have been in range 74% of the tests done and those out of range were highest 0.3 over and lowest 0.2 under, Several were within 0.1 of target. And no I don't ever bother with watching what I eat or drink. Smug person. What is interesting is that if I fell out of range it took the system at least two or three go's to get me back due to yo yo effect whereas if I ignored what they said and carried on with the dose I have always taken it returned much quicker. If I look at the last three years after I realised the above my results are better than 83%.

  • Agree absolutely with you Beancounter. It is reassuring to have it confirmed. I have been on Warfarin for 5 years and always my INR ihas been in range. I self -test and would like to self- regulate but the clinic does not approve this. I only have to do my INR every 3 months and every other time I go to the clinic where they check my machine against theirs. 

    By the way I take all my tablets together in the morning including the Warfarin. That way I never forget it.

  • I found the article very interesting. There were 3 points in particular:

    1. The TTR in Sweden was only 68% but they still got good results. In another article I read, Scotland for instance is 72%! Maybe irn-bru stabilises warfarin?! What is shocking is that it's only 53.7% in the States.

    2. Xiaoxi Yao, in a related article, has found that more than half of people taking NOACs are compliant less than 80% of the time., i.e. considerably reducing their effectiveness.

    3. The pivotal NOAC trials had intracranial bleeding on warfarin at a rate of 0.70%-0.85% compared with the real world study above of 0.44%. Similarly all-cause mortality on warfarin was 2.2% in this trial, which is about half that in the warfarin and NOAC-treated patients in the NOAC trials (3.9%–4.9% and 3.5%–4.5%, respectively). If warfarin had had these results in the NOAC trials, I very much doubt they would have been approved. Hmmm...

  • Thank you, very interesting reading. 

  • as long as you can regularly check your INR I think wafarin is the best way to go.

  • Did the report define what they meant by stayed within range? This is NOT necessarily the same between different studies. In addition, it may well be easier to stay in range if your range is lower, than if it is higher. It is well known that it is easier to adjust dosage when INR is low, than when INR is high.

    I have real problems with tight ranges. INR=1  is much too tight. I would love to see research showing what the natural random variability is in this. I suspect that for many people, the natural range is 2, not 1. I am amazed that the medical profession has not given more attention to this basic question. Unless you know what the background natural range is, you are wasting your time with dose adjustments, and being counter productive because premature adjustments can create and even magnify swings. And as BobW says, ignoring an  ut of range your body comes back into range without changing dosage. Homeostasis. The natural tendency for chaotic systems to regress towards the mean without interference. I have had swings from 2.2 to 5.5 in the past, then I stabilized, no dose change.

    Interesting that my favourite reference on this subject recognises the tendency and suggests that the first, and sometimes even the second result out of range is safe to ignore and you only act if you have three results out of range.

    My modification of that, which you will be hard put to find in the public literature, is 'stepping' ie on the second out of range result, I will make a slight change for three days, then return to normal.

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