Study Design Strategies to Evaluate
Pharmacogenetic Testing and
www.WarfarinDosing.org
Brian F. Gage
MD, MSc (HSR)
Department of Internal Medicine, Division of General Medical Sciences
Washington University School of Medicine
Friday, January 18, 2008, 12:30–1:30 pm
GEMS classroom, 3rd Floor in
Shriner's Building
Coffee, tea, and cookies will be provided
Abstract
Warfarin sodium (Coumadin(tm) and others) is a common blood thinner used to
treat or prevent thromboembolic events in patients at high risk for clotting.
Polymorphisms of two known genes (CYP2C9 and VKORC1) contribute 30% to the
variation in dose requirements by altering warfarin metabolism and
sensitivity. In recognition of warfarin's pharmacology, the FDA changed its
labeling to encourage, but not require pharmacogenetic testing when warfarin
is initiated. To prevent bleeding due to overdose and thrombosis from
under-dosing, we developed pharmacogenetic algorithms that incorporate
genotype and traditional factors available when warfarin is initiated.
Prospective, open-labeled use of the algorithms demonstrates greater accuracy
than clinical dosing and suggests a 20% reduction in clinical adverse events.
However, a multi-centered, randomized controlled trial of clinical and
pharmacogenetic approaches has yet to be done.
In this talk we will discuss study design strategies for a multicentered,
randomized trial of warfarin therapy. In particular, we will discuss:
methods of double-blinding, a study website (www.WarfarinDosing.org), use of
an intermediate outcome (INR control), enhancement of certain genotypes, and
the efficiency of testing for an interaction between genotype and group.
This work is joint with
Petra (Jacobsen) Lenzini, MSc (GEMS).