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The comment of Tripodi and Moia regarding the inaccuracy of the International Normalized Ratio (INR) above 4.5 is correct, as calibration of thromboplastin is performed with plasmas from patients with mostly adequate anticoagulation (INR 1.5–4.5) [1]. They are concerned that our suggestion in the latest edition of the American College of Chest Physicians clinical practice guidelines regarding reversal of asymptomatic high INR with vitamin K is misleading [2].

The basis for our suggestion to abstain from reversal with vitamin K of asymptomatic INRs between 4.5 and 10 is derived from four randomized controlled trials [3-6]. In three of those, the population studied had INRs of 4.5–10.0, whereas the smallest study included patients with INRs between 6.0 and 12.0 [4]. The negative results are driven by the largest trial [5]. One of the rules when authoring guidelines is to restrict the recommendations or suggestions to the population studied. Therefore, it is necessary that we, in our conclusion, address the population of patients with asymptomatic high INRs of 4.5–10. In addition, for the patients with very high INRs, we identified two cohort studies, both including patients with INRs above 10.0 [7, 8].

The second point to be made is that we ‘suggest’ rather than ‘recommend’, as the quality of the evidence in the randomized trials was only moderate. This was based on serious imprecision with wide confidence intervals for the risk of major bleeding, thromboembolism, or death. The implications of a 2B suggestion are as follows [9]:

Best action may differ, depending on circumstances or patient or societal values. Higher-quality research may well have an important impact on our confidence in the estimate of effect, and may change the estimate.

The implications of a 2C suggestion are as follows [9]:

Other alternatives may be equally reasonable. Higher-quality research is likely to have an important impact on our confidence in the estimate of effect, and may well change the estimate.

It is therefore clear that the treating physician should make an individual judgement in these cases on whether to treat or not.

It would be reasonable to add, in a future edition of the guidelines, the caution pronounced by Tripodi and Moia that high INRs are inherently inaccurate.

Disclosure of Conflict of Interests

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  2. Disclosure of Conflict of Interests
  3. References

The authors state that they have no conflict of interest.

References

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  2. Disclosure of Conflict of Interests
  3. References
  • 1
    Tripodi A, Moia M. The accuracy of the International Normalized Ratio and the American College of Chest Physicians recommendations on the use of vitamin K to reverse over-anticoagulation. J Thromb Haemost 2012; 10: 22078.
  • 2
    Holbrook A, Schulman S, Witt DM, Vandvik PO, Fish J, Kovacs MJ, Svensson PJ, Veenstra DL, Crowther M, Guyatt GH. 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: e152S84S.
  • 3
    Ageno W, Crowther M, Steidl L, Ultori C, Mera V, Dentali F, Squizzato A, Marchesi C, Venco A. Low dose oral vitamin K to reverse acenocoumarol-induced coagulopathy: a randomized controlled trial. Thromb Haemost 2002; 88: 4851.
  • 4
    Ageno W, Garcia D, Silingardi M, Galli M, Crowther M. A randomized trial comparing 1 mg of oral vitamin K with no treatment in the management of warfarin-associated coagulopathy in patients with mechanical heart valves. J Am Coll Cardiol 2005; 46: 7323.
  • 5
    Crowther MA, Ageno W, Garcia D, Wang L, Witt DM, Clark NP, Blostein MD, Kahn SR, Vesely SK, Schulman S, Kovacs MJ, Rodger MA, Wells P, Anderson D, Ginsberg J, Selby R, Siragusa S, Silingardi M, Dowd MB, Kearon C. Oral vitamin K versus placebo to correct excessive anticoagulation in patients receiving warfarin: a randomized trial. Ann Intern Med 2009; 150: 293300.
  • 6
    Crowther MA, Julian J, McCarty D, Douketis J, Kovacs M, Biagoni L, Schnurr T, McGinnis J, Gent M, Hirsh J, Ginsberg J. Treatment of warfarin-associated coagulopathy with oral vitamin K: a randomised controlled trial. Lancet 2000; 356: 15513.
  • 7
    Crowther MA, Garcia D, Ageno W, Wang L, Witt DM, Clark NP, Blostein MD, Kahn SR, Schulman S, Kovacs M, Rodger MA, Wells P, Anderson D, Ginsberg J, Selby R, Siragusa S, Silingardi M, Dowd MB, Kearon C. Oral vitamin K effectively treats international normalised ratio (INR) values in excess of 10. Results of a prospective cohort study. Thromb Haemost 2010; 104: 11821.
  • 8
    Gunther KE, Conway G, Leibach L, Crowther MA. Low-dose oral vitamin K is safe and effective for outpatient management of patients with an INR>10. Thromb Res 2004; 113: 2059.
  • 9
    Guyatt GH, Norris SL, Schulman S, Hirsh J, Eckman MH, Akl EA, Crowther M, Vandvik PO, Eikelboom JW, McDonagh MS, Lewis SZ, Gutterman DD, Cook DJ, Schunemann HJ. 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: 53S70S.