Pragmatic Trials Collaborative

Measuring What Matters

Trials In Progress


INRange is our inaugural pragmatic trial. It is primarily intended to pilot our recruitment methods but also allows us to learn whether the safety and effectiveness of the anticoagulant warfarin varies with the time of day it is ingested.

See the poster from the 61st Annual Scientific Assembly.

The effect of diet and medication timing on anticoagulation stability in the users of warfarin: the "INRange" RCT

Why would we want to look at this?

Warfarin is used to reduce the risk of clotting disorders (e.g. stroke) in patients who are predisposed to forming clots. It accomplishes this by interfering with the vitamin K dependent production of clotting factors in the liver1. High oral intake of dietary vitamin K can overcome the effect of warfarin and variability of vitamin K intake is believed to cause fluctuation in warfarin’s effectiveness2. Currently patients are told to take their warfarin at dinnertime – the same time of day in which vitamin K content in meals is most highly variable. Given vitamin K has an ultra short (2.5 hour) half-life and is cleared from the body quickly3, given warfarin might be more active around the time of day it is ingested (when the liver is exposed to higher warfarin concentrations), and given typical breakfast foods have very little vitamin K, it is possible that taking warfarin at breakfast when the competing vitamin K influence would be more consistent (consistently low) might lead to a more stable anticoagulant effect. This is a highly speculative hypothesis but no studies have ever been conducted evaluating whether the time of day warfarin is ingested matters to its effectiveness. Specifically, this study looks at the proportion of time patients spend outside of the therapeutic INR range (the blood test that assesses warfarin’s effectiveness) and determines whether the proportion of time outside this desired range is lessened when patients take their warfarin in the morning. If so, patients making such a switch may have both less risk of adverse effects (bleeding disorders), and greater effectiveness (less risk of stroke) for no extra cost or inconvenience.

Trial registration: NCT02376803

The Team

the team


INRange is currently completing follow-up with 236 primary care providers having recruited across British Columbia and Alberta (¾ in Alberta). Final results should be available in the spring of 2017.

  1. Hirsh J, Fuster V, Ansell J, Halperin JL, American Heart A, American College of Cardiology F. American Heart Association/American College of Cardiology Foundation guide to warfarin therapy. Circulation. Apr 1 2003;107(12):1692-1711.
  2. Franco V, Polanczyk CA, Clausell N, Rohde LE. Role of dietary vitamin K intake in chronic oral anticoagulation: prospective evidence from observational and randomized protocols. The American journal of medicine. May 15 2004;116(10):651-656.
  3. Olson RE. The function and metabolism of vitamin K. Annual review of nutrition. 1984;4:281-337.