Reversal of Warfarin

Our question was:  given a generally healthy asymptomatic patient on warfarin for afib who is sent to the ED because of an elevated INR of 8 but who has heme + brown stool and a Hgb of 11, what is the appropriate intervention (hold warfarin only, or also treat with vitamin k, and if so, at what dose/route)?  What are the risks of bleeding, and what are the thrombotic risks?

First, as a reminder, our patient has a CHADS score of 1.  This represents an annual stroke risk of 2.8% for patients with afib (see below), so warfarin treatment is reasonable.   Unfortunately, even in warfarin clinics, INRs are outside the therapeutic range one third to one half of the time.  It’s well accepted that bleeding risk increases with increasing INR, especially when INR >4.  What is our patient’s risk of bleeding?   

Garcia DA, Regan S, Crowther M, Hylek EM. The risk of hemorrhage among patients with warfarin-associated coagulopathy. J Am Coll Cardiol. Feb 21 2006; 47:804-808

evaluated a cohort of 979 patients with a first episode of INR >5.  During 30 day followup, 0.96% of patients with an INR >5<9 experienced major hemorrhage.  When the INR >/= to 9, the risk of bleeding increased to 9.5%.  Only 9% of patients in this study received vitamin k (mostly 2.5 mg or less).  So, a good place to start:  there’s about a 1% 30 day risk of major bleeding when your INR >5 <9.  There were no ICHs in this study.  In the Aiyagari background article on ICH/warfarin, a range of 0.3-0.6% per year risk of ICH while on warfarin is quoted, but as Harwood pointed out, the risk of ICH skyrockets in the elderly.

So, how should we protect our patient?  The meta-analysis,

Dezee KJ, et al. Treatment of excessive anticoagulation with phytonadione (vitamin K): a meta-analysis. Arch Intern Med. Feb 27 2006; 166:391-397

evaluated all of the RCTs and prospective nonrandomized trials using vitamin K to treat patients without major hemorrhage with an INR >4 on oral anticoagulants, from 1985-2004.  Unfortunately, as they admit, the quality of studies available was fair to poor, leading to a concern of “garbage in, garbage out.”  There were a few limited conclusions.  Subcutaneous vitamin K is no better than placebo.  Just don’t use it (and this is also part of the 2008 ACCP guidelines).  Oral and IV vitamin K worked about equally as well in this meta-analysis, but with the risks of anaphylactoid reactions with IV vitamin K, you should choose oral if the patient isn’t having major bleeding.  Most (about 80%) patients with INR <10 who receive oral vitamin K (2.5 mg or less) will have an INR < 4 in 24 hours.  That’s fine, but does giving vitamin K prevent bleeding?  Does giving vitamin K cause an increased risk of thrombosis? Sorry, but no answers from this meta-analysis due to the fair/poor quality of the included studies.

So, our third article came out in 2009.  It’s a large study of over 700 non-bleeding patients with INRs of 4.5 to 10, trying to look whether or not giving low dose vitamin K (1.25 mg) decreases bleeding risk.

Crowther MA, et al. Oral vitamin K versus placebo to correct excessive anticoagulation in patients receiving warfarin: a randomized trial. Ann Intern Med. Mar 3 2009; 150:293-300  

At 90 days, this study demonstrated no significant difference in the rates of bleeding between patients receiving 1.25 mg vitamin K vs. those receiving placebo.  The study was under-powered to detect a difference in major bleeds, although interestingly, more major bleeds occurred in the vitamin K group (likely chance, but the major bleeds all happened >30 days out-could there be issues with re-starting warfarin and maintaining a therapeutic INR after receiving vitamin K?).  Although death and thromboembolism were rare and rates were balanced between the 2 groups, these were secondary outcomes and no firm conclusions are possible.  Erik Kulstad made several important points about the methodology:  there are issues of external validity (ability to apply study conclusions to your own patients):  patients enrolled in studies are different-they are compliant, in general healthier, and in this case had amazing followup with multiple phone calls, likely identifying problems/bleeding more frequently than in an unselected population.  Also, we are missing an explanation of who and how many patients were not included in the study-who are the ineligible and missed patients?

So, coming back to our patient….after much discussion, we took votes on 2 different patients:  first, our PICO patient, but without heme positive stools.  Everyone in the room agreed to send him home, and all except one would not give him vitamin K.  When the patient had heme + stools (occult GI bleed, no melena, and stable/asymptomatic), still most would send him home, although now many would given low dose vitamin K (1-2.5 mg, orally).  Again, as Harwood pointed out, you only need to change one variable to dramatically change risk and outcome and disposition (old, or melena, or poor social situation, or INR 11).  Still, we do see a ton of patients like our PICO guy, and I believe this JC supports being more comfortable with doing less than many us (me included) may have done in the past.  Interestingly, in the most recent ACCP guidelines from 2008, although the table looks similar to 2004, the doses of vitamin K recommended are half of the 2004 recs for patients without significant bleeding (both INR 5-9, and INR >9). 

Last point:  we chose the PICO patient deliberately:  the heme + stools and hgb 11 means that he isn’t really exactly  like any of the patients in our studies.  There is no “right answer” on how to treat him. Involving the patient in his medical decisions is the “third circle” of EBM (evidence, clinical experience, and patient values).  Maybe he is really afraid of a thrombotic stroke or MI.  Maybe he doesn’t have insurance and isn’t going to get his INR rechecked tomorrow.  You get the idea.



CHADS score for background:


 C   Congestive heart failure 1
 H  Hypertension (or treated hypertension) 1
 A  Age >75 years 1
 D  Diabetes 1
 S2  Prior Stroke or TIA 2
Annual Stroke Risk
CHADS2 Score  Stroke Risk %      95% CI      
0 1.9  1.2–3.0
1 2.8  2.0–3.8
2 4.0  3.1–5.1
3 5.9  4.6–7.3
4 8.5  6.3–11.1
5 12.5  8.2–17.5
6 18.2 10.5–27.4