Anticoagulation: increased bleeding with supratherapeutic INR and high therapeutic ranges.

Clinical bottom line (level 2b)

  1. A tenth of patients on anticoagulation for 24 months had a severe bleed. Less than 2% had a life-threatening or fatal bleed.
  2. Patients on warfarin were more likely to bleed if:
    • their treatment was more intense (INR~3 to 4) (NNF = 19 for 3 years)
    • they had supratherapeutic INR
Fihn et al: Annals for Internal Medicine 1996; 124 (11): 970-979
Expires June 2003

The study

Retrospective cohort study with objective outcomes, adjusted for confounding factors, not validated in an independent set of patients.

Setting: six anticoagulation clinics, USA

2376 patients (aged mean 58 years, 73% male) started on anticoagulation (INR 2.6 to 4.0) over 24 months

Excluded if
  • on warfarin for <6 weeks



    • Factors studied:
  • severe bleed, life-threatening or fatal bleed
  • intensity of treatment (INR 2.0 to 3.0 vs 3.0 to 4.0)
  • deviation in prothrombin time from therapeutic range
  • deviation in prothrombin time from therapeutic range




    • Multivariate regression was used to adjust for confounding factors.

    100% followed for 2 to 3 years
    Outcomes studied:
  • severe bleed
  • life-threatening or fatal bleed

    • A prospective cohort was combined with the retrospective cohort. 425 patients in the retrospective cohort and 1875 originally in a randomised controlled trial, in the prospective cohort.

    The evidence

    outcome time to outcome number of patients/total number %
    (95% CI)
    severe bleed 2 to 3 years 222/2376 9.34%
    (8.17% to 10.5%)
    life-threatening or fatal bleed 2 to 3 years 37/2376 1.56%
    (1.06% to 2.06%)

    prognostic factor for
    severe bleed     		time to outcome adjusted RR
    (95% CI)    		 NNF+
    (95% CI)
    intensity of treatment (INR 2.0 to 3.0 vs 3.0 to 4.0) 2 to 3 years 1.55
    (1.17 to 2.06)     		19
    (10 to 63)
    deviation in prothrombin time from therapeutic range 2 to 3 years 17.9
    (9.58 to 33.6)     		1
    (0.3 to 1)

    prognostic factor for
    life-threatening or fatal bleed     		time to outcome adjusted RR
    (95% CI)    		 NNF+
    (95% CI)
    deviation in prothrombin time from therapeutic range 2 to 3 years 27.3
    (9.42 to 79.1)     		2
    (1 to 8)

    • Sites of bleeding were: GU 24%, GI 22%, skin/soft tissues 19%.

    Comments

    1. No differences noted when retrospective or prospective cohorts were analysed separately- therefore, they were combined.
    2. Age was not found to be an independent risk factor.

    Citation

    1. Fihn SD, Callahan CM, Martin DC, et al: The risk for and severity of bleeding complications in elderly patients treated with warfarin. Annals for Internal Medicine 1996; 124 (11): 970-979
    Search Terms: atrial fibr* and anticoag* in Cochrane
    Contributor: Chris Ball and Clare Wotton, June 2000
    Reviewer:

    Clinical Question.
    Patient on anticoagulation
    Intervention or Exposure prognostic factors
    Outcome severe bleeding