Prothrombin Times Outside the Therapeutic Range in Otherwise Stable Patients
Condition: Atrial Fibrillation; Venous Thromboembolism; Ischemic Stroke; Myocardial Infarction
MeSH terms: Ischemic Stroke; Atrial Fibrillation; Myocardial Infarction; Thromboembolism; Venous Thromboembolism; Infarction
Intervention: warfarin; warfarin
Intervention description: No change: Continue without any change in spite of prothrombin time outside the therapeutic range.; Change: Increase one dose in case prothrombin time is below the therapeutic range; delete or reduce one dose in case prothrombin time is above the therapeutic range.
Intervention MeSH terms: Warfarin
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 160.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: warfarin; dosing; prothrombin time; Heart valve prosthesis

Summary:

      Warfarin is very effective for the prevention of blood clots (thrombosis). A test of
      coagulation, the prothrombin time (PT) is used to monitor the effect. The PT response to
      warfarin can fluctuate as a result of interactions with a large number of other drugs, food
      or herbal agents as well as for no apparent reason. Thus, frequent monitoring of the PT and
      dose adjustments according to the results are required. One third of our patients remain on
      the same maintenance dose over 6 months. However, also these patients sometimes have a PT
      result moderately outside the therapeutic range without any obvious explanation. Too short
      PTs may be due to missed dose(s) or more dark green vegetables in the diet. Too long PTs may
      be due to a course of antibiotic therapy or less dark green vegetables. Laboratory errors may
      also occur and can cause deviations in any direction. Most likely, unnoticed fluctuations in
      the PT occur as well between the time points of monitoring.

      There are no guidelines on how to manage the treatment in this situation but there are some
      typical "behaviours".

      Behavior A: Some physicians simply let the patient continue with the same dose. "It is
      extremely unlikely that the very temporary dose adjustment has any effect on the PT result 4
      weeks later and this is a "cosmetic procedure"." Behavior B: Others recommend the patients to
      take ½ - 1 additional dose in case of short PT and to skip a dose or take half dose in case
      of long PT, and thereafter to continue with the usual dose. "The investigators need to
      quickly correct the temporary aberration in order to avoid thrombotic or bleeding
      complications the next few days.

      This may seem like an issue of no importance. The investigators are however performing a
      series of studies to evaluate if these stable patients can be managed with blood tests less
      often than every 4 weeks. For that purpose it is important to know how often and why aberrant
      results occur, the implication and to what extent they can be ignored.

      The investigators hypothesis is that in patients with very stable PT-results and unchanged
      dose for 3 months, should continue with exactly the same maintenance dose, even when the
      result unexpectedly is slightly above or below the therapeutic range. The investigators
      believe that most of these occasional PT-results outside the therapeutic range are due to
      laboratory errors, perhaps missed doses by the patient or temporary change in diet or
      medications.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Patients on long-term warfarin (for prophylaxis of arterial embolism in patients with
             atrial fibrillation or mechanical heart valve replacement, or secondary prophylaxis
             after VTE) with a target INR of 2.0-3.0 or 2.5-3.5,

          2. Anticoagulant therapy managed by the clinic (HHS - General Hospital) for at least 3
             months prior to enrolment, and

          3. Maintenance dose of warfarin unchanged for the previous 3 months or longer.

          4. The INR result is outside the therapeutic range as follows:

        For those with target 2.0-3.0: Either an INR of 1.5-1.9 or an INR of 3.1-4.4. For those
        with target 2.5-3.5: Either an INR of 1.5-2.4 or an INR of 3.6-4.4.

        Exclusion Criteria:

          1. Age <18 years,

          2. Long-term (>1 week) change in any other medication

          3. Long-term (>1 week) change in diet, especially regarding green vegetables.

          4. Attending physician believes the patient is not suitable for the study (e.g.
             psychiatric disorder, history of non-compliance),

          5. Failure to obtain telephone consent.