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Schulman S, Parpia S, Stewart C, et al. Warfarin Dose Assessment Every 4 Weeks Versus Every 12 Weeks in Patients With Stable International Normalized Ratios. Ann Intern Med 2011; 155: 653-59.

“See you in four weeks!” This has been a common ending to most anticoagulation clinic appointments over the years.  But perhaps it’s time for this routine to change?  A welcomed 12-week holiday may be coming for many patients based on evidence from a recent study as well as a new recommendation in the recently released 9th edition of the American College of Chest Physicians (ACCP) Antithrombotic Therapy and Prevention of Thrombosis Guidelines (AT9).2,3  But before you start adding a “12 weeks” follow-up check box to your anticoagulation clinic check out form, let’s assess whether the evidence is sufficient to trigger a sweeping change in practice. 

In an effort to determine the viability of 12 week warfarin follow-up, Shulman and colleagues randomly assigned 250 patients to either traditional (4 week) or extended interval (12 week) international normalized ratio (INR) assessments.2  Patients were recruited from a single center in Canada and were included if they had gone six months prior to randomization without a change in their warfarin dose.  During the study, all patients had INRs drawn every 4 weeks for 12 months.  In the 4-week assessment group, all INRs were reported to the clinician investigator.  In the 12-week assessment group, INRs were reported every 4 weeks to the investigators but 2 “sham” INRs, within or near the target range, were reported at weeks 4 and 8.  The true INR was provided to the clinician investigator at week 12.  If the true INR, which was reviewed by the study coordinator, was an “extreme” value (INR >4.5) the sham was not reported and the investigator was alerted.  In both groups, patients were contacted every 4 weeks and interviewed by telephone regarding warfarin therapy related issues (e.g. changes in health status, medications, diet, and bleeding).

Twelve-week INR assessment was determined to be noninferior to 4-week INR assessment with regard to percent time in therapeutic range (74.1% vs. 71.6%, respectively; p=0.02).   No significant differences were seen in secondary endpoints including the number of extreme INRs or major bleeds, thromboembolic events, and deaths (although the authors admit that the study clearly was not powered to detect meaningful changes in these outcomes).   Dose changes were 18.5% more common in the 4-week group (p=0.004 for superiority).

Based on these data, one cannot argue with the authors’ conclusion that 12-week INR assessment is safe and noninferior to 4-week assessment.  However, it is important to recognize the limitations of this study design, which the authors clearly outline, prior to considering this evidence as a green light to start wholesale 12-week warfarin follow-up in stable patients.  These limitations are several fold.

Most importantly the intervention does not reflect how 12-week follow-up would be actually implemented in clinical practice.  Patients assigned to the 12-week follow-up group were contacted every 4 weeks.  This would not happen if patients were truly “left on their own” for 12 weeks.  There may be a certain security in close follow up and we don’t really know how patients would fair “outside the nest” for 12 full weeks.  Second, there was a fail-safe mechanism in the study with “bail out” INR alerts for “extreme” values.  While the bail-out alert was required only twice, this level of oversight, along with every 4 week phone follow up, seem like training wheels on a kid’s bike.  Sure, you’re riding, but you’re not going to fall down and scrape your knee!

With these limitations, it is somewhat puzzling that this data was sufficient to move the ACCP AT9 expert panel to recommend:

For patients taking [vitamin K antagonists (VKA)] therapy with consistent stable INRs, we suggest an INR testing frequency of up to 12 weeks rather than every 4 weeks.3   

Appropriately, the evidence grade for this recommendation is only 2B  (e.g. moderate quality evidence in which there is less certainty about the magnitude of the benefits and risks, burden and costs).3,4  The AT9 authors concede that the “best action may differ depending on circumstances or patient or societal values” and better research might alter the recommendation.4  So basically, you could follow the recommendation but we would know better how to proceed if we had more robust studies.   We must also acknowledge that our traditional 4-week follow-up recommendation is based on conventional wisdom rather than clear evidence.

Despite its many limitations – relatively small, single center, surrogate endpoints, methods that don’t reflect how the intervention would be implemented in clinical practice – this study still provides us with some useful insights.1,2  While the lack of “firm” data might make indiscriminant implementation unwise, clinicians might find appropriate circumstances when these findings apply to individual patients.  Perhaps 12-week follow-up is reasonable in stable, well-educated patients who are aware of the need and are able to pro-actively alert their anticoagulation provider of changes in medications, health status, and diet as well as pending invasive procedures.

Extending the follow up period is of significant importance now that new oral anticoagulants have entered the market.  Perhaps in order stay fresh and competitive, warfarin needs a “same product, new look” makeover.  This will allow less frequent monitoring in a stable patient who may not be an ideal dabigatran, rivaroxaban, or apixaban candidate but wants to scrap warfarin due to frequent visits to the coag clinic.  The 12-week follow-up option may make the choice to stay with warfarin therapy more attractive for some patients … and less resource intensive for us.

Clearly more evaluation of “extended interval” follow up in clinical practice is needed.2  However, until that data is available, selective and cautious application of extended interval follow-up seems reasonable.  But, as is always the case with warfarin, patient education and empowerment are paramount.  Engaging patients as active participants in decision-making is likely a necessary ingredient for success with extended interval INR assessment.

Case Study: How would you apply AT9 to this patient?

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1. Ansell J, Hirsh J, Hylek E, et al. Pharmacology and Management of the Vitamin K Antagonists. American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). 2008; 133: 160S-198S.

2. Schulman S, Parpia S, Stewart C, et al.  Warfarin Dose Assessment Every 4 Weeks Versus Every 12 Weeks in Patients With Stable International Normalized Ratios. Ann Intern Med 2011; 155: 653-59.

3. Holbrook A, Schulman S, Witt DM, et al. Evidence-Based Management of Anticoagulant Therapy Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141: 52S-184S.

4. Guyatt GH, Norris SL, Schulman S, et al. Methodology for the Development of Antithrombotic Therapy and Prevention of Thrombosis Guidelines Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141: 53S-70S.