Anticoagulation: more patients on a five day anticoagulation course died than on a ten day one.

Clinical bottom line (level 1b)

  1. Patients who received heparin for five days and had warfarin started on the first day of treatment, had a higher mortality than patients that had heparin for ten days and started warfarin on the fifth day (NNT = 16 at 3 months) .
  2. There was no clear difference in major haemorrhage, recurrent deep vein thrombosis, deaths from haemorrhage or heparin-induced thrombocytopenia.
Hull et al: New England Journal of Medicine 1990; 322 (18): 1260-1264
Expires June 2003

The study

Double-blinded concealed randomised trial with intention-to-treat
Setting: university hospital, Canada

199 patients (aged >60 years, 53% female) proximal deep vein thrombosis proven by venogram

Excluded if
  • active bleeding disorder
  • heparin iv given already for >24 hours
  • unable to be followed up


    • Note:
  • Patients were stratified according to whether or not they had a history of venous thrombosis, and to absence or presence of one or more risk factors for bleeding.


    • Control Group: (n = 100, 100 analysed): heparin and warfarin for 10 days, starting on day 5. Heparin overlapped warfarin by at least 5 days.
    Experimental Group: (n = 99, 99 analysed): heparin and warfarin for 5 days, started on day 1. Heparin overlapped warfarin by at least 5 days.
    Patients were anticoagulated using the following regimen: heparin- 5000 units bolus iv, then 40, 000 units/24 hours if 'low-risk' patient, or 30,000 units if 'high-risk' patient. aPTT monitored; warfarin- therapeutic range INR 2.0-3.0. Heparin continued until INR = 2.0. Anticoagulated for 12 weeks.
    100% followed for 3 months
    Outcome notes:
    • major bleed : > or = 2 units transfused or retroperitoneal, intracranial or at major prosthetic joint
    • heparin-induced thrombocytopenia : platelet count <150

    The evidence

    Outcome Time to outcome CEREERRRR
    (95% CI)    		ARR
    (95% CI)    		NNT
    (95% CI)
    major bleed 3 months 6
    (6.00%)    		 7
    (7.07%)    		 -18%
    (-240% to 59%)    		 -1.07%
    (-7.94% to 5.80%)    		 -93
    (NNT = 17 to infinity;
    NNH = 13 to infinity)
    recurrent deep vein thrombosis 3 months 7
    (7.00%)    		 7
    (7.07%)    		 -1%
    (-177% to 63%)    		 -0.07%
    (-7.18% to 7.04%)    		 -1400
    (NNT = 14 to infinity;
    NNH = 14 to infinity)
    death 3 months 2
    (2.00%)    		 8
    (8.08%)    		 -304%
    (-1750% to 12%)    		 -6.08%
    (-12.1% to -0.05%)    		 -16
    (-1900 to -8)
    deaths from bleeding 3 months 0
    (0.00%)    		 2
    (2.02%)    		 100%
    (% to %)    		 -2.02%
    (-4.79% to 0.75%)    		 -50
    (NNT = 133 to infinity;
    NNH = 21 to infinity)
    heparin-induced thrombocytopenia 3 months 2
    (2.00%)    		 3
    (3.03%)    		 -52%
    (-790% to 74%)    		 -1.03%
    (-5.38% to 3.32%)    		 -97
    (NNT = 30 to infinity;
    NNH = 19 to infinity)

    Comments

    1. Is the shorter heparin therapy, or the earlier warfarin dosing the main cause for the increase in mortality? Gallus et al have shown that starting warfarin on day one is safe, suggesting the difference is due to the shorter heparin time. Would seven days of heparin be enough, or two days of heparin after INR in therapeutic range?
    2. This study offers no information as to the length of overlap required for heparin and warfarin.

    Citation

    1. Hull RD, Raskab GE, Rosenbloom D, et al: Heparin for five days compared with ten days in the initial treatment of proximal venous thrombosis. New England Journal of Medicine 1990; 322 (18): 1260-1264
    Search Terms: anticoag* in Cochrane
    Contributor: Chris Ball and Clare Wotton, June 2000
    Reviewer:

    Clinical Question.
    Patient proximal DVT
    Intervention or Exposure five days of heparin and warfarin
    Comparison ten days of heparin and warfarin
    Outcome recurrent DVT, major bleed