Prothrombin Times Outside the Therapeutic Range in Otherwise Stable Patients (FORESPEAK-0)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00814177
Recruitment Status : Completed
First Posted : December 24, 2008
Results First Posted : November 25, 2009
Last Update Posted : August 1, 2012
Information provided by (Responsible Party):
Sam Schulman, McMaster University

December 23, 2008
December 24, 2008
October 7, 2009
November 25, 2009
August 1, 2012
July 2006
January 2009   (Final data collection date for primary outcome measure)
Number of Patients With Prothrombin Time Results Within the Therapeutic Range After 2 Weeks [ Time Frame: 2 weeks ]
The number of patients with "follow-up INRs" within the therapeutic range was compared for patients with a single dose skipped/reduced/added versus patients with no change of dose.
Prothrombin Time Results Within the Therapeutic Range After 2 Weeks [ Time Frame: Two weeks ]
Complete list of historical versions of study NCT00814177 on Archive Site
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Prothrombin Times Outside the Therapeutic Range in Otherwise Stable Patients
Management of Prothrombin Times Outside the Therapeutic Range in Patients on Warfarin and With Otherwise Stable Levels

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.


Thrombosis Service at HHS - General Hospital. This center monitors the warfarin treatment for 1300 patients in the region. These patient regularly go to a laboratory where they live. Test results (INR-results) are faxed to the Thrombosis Service, which calls the patient the same day to inform them of the results, how to continue dosing the warfarin and when to go for the following blood test.

Phase 2
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
  • Atrial Fibrillation
  • Venous Thromboembolism
  • Ischemic Stroke
  • Myocardial Infarction
  • Drug: warfarin
    No change: Continue without any change in spite of prothrombin time outside the therapeutic range.
    Other Name: Coumadin
  • Drug: warfarin
    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.
    Other Name: Coumadin
  • Experimental: No change
    Intervention Drug warfarin no change in the dose is performed
    Intervention: Drug: warfarin
  • Active Comparator: Change
    Intervention Drug Warfarin One dose increased if subtherapeutic level; one dose deleted or reduced if supratherapeutic level
    Intervention: Drug: warfarin
Schulman S, Melinyshyn A, Ennis D, Rudd-Scott L. Single-dose adjustment versus no adjustment of warfarin in stably anticoagulated patients with an occasional international normalized ratio (INR) out of range. Thromb Res. 2010 May;125(5):393-7. doi: 10.1016/j.thromres.2009.07.006. Epub 2009 Jul 29.

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
April 2009
January 2009   (Final data collection date for primary outcome measure)

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.
Sexes Eligible for Study: All
18 Years and older   (Adult, Older Adult)
Contact information is only displayed when the study is recruiting subjects
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Sam Schulman, McMaster University
Hamilton Health Sciences Corporation
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Principal Investigator: Sam Schulman, MD, PhD McMaster University
McMaster University
July 2012

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP