Official Title: “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.

Study Type: Interventional

Study Design: Treatment, Randomized, Open Label, Active Control, Parallel Assignment, Efficacy Study

Study Primary Completion Date: July 2009

Setting:

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.

Inclusion criteria:

Patients with unchanged maintenance dose for the previous 3 months and an INR result above the therapeutic range - but not higher than 4.4 - or below the therapeutic range - but not below 1.5.

Exclusion criteria:

Reasons for a sustained effect on the INR result (change in chronic medications or more than transient change in diet or eating habits.) Patient declines telephone consent.

Intervention(s) in this Clinical Trial

• Drug: warfarin
  • No change: Continue without any change in spite of prothrombin time outside the therapeutic range.
• Drug: warfarin
  • Change: Increase one dose in case prothrombin time is below the therapeutic range; delete or reduce one dose in case protrombin time is above the therapeutic range.

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: No change
  • Intervention Drug warfarin no change in the dose is performed
• Active Comparator: Change
  • Intervention Drug Warfarin One dose increased if subtherapeutic level; one dose deleted or reduced if supratherapeutic level

Primary Measures

• Prothrombin time results within the therapeutic range after 2 weeks
  • Time Frame: Two weeks
    Safety Issue?: Yes

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.

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: Hamilton Health Sciences

Overall Clinical Trial Officials and Contacts

Sam Schulman, MD, PhD Principal Investigator McMaster University  

Overall Contact: Sam Schulman, MD, PhD 1-905-5270271 schulms@mcmaster.ca

Information obtained from ClinicalTrials.gov on July 02, 2009

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00814177

Study ID Number: HRC060425

ClinicalTrials.gov Identifier: NCT00814177

Health Authority: Canada: Ethics Review Committee