Download the Monday Daily - American Association for Clinical ...

Opponents Want More Data
Warfarin debate, from page 1
The debate format represents
a new twist to the
standard sypmposia presented
at the AACC Annual
Meeting. Everyone who
attends the debate will get
a chance to weigh in on the
michael Hallworth issue, Hallworth said. The
audience will vote both before and after the
debate to determine if the speakers were
able to sway any opinions.
Proponents Emphasize Potential
Shiew-Mei Huang, PhD,
Deputy Director of FDA’s
Office of Clinical Pharmacology,
will propose a motion
in favor of more wide-
shiew-mei Huang
spread testing, reflecting
FDA’s stance on the issue.
FDA’s label language, which indirectly suggests
that physicians consider pharmacogenomic
testing to determine initial warfarin
dose, is based on data showing that doing
so keeps warfarin patients’ INRs in an acceptable
range of 2–3. In the absence of definitive
data from randomized, controlled
trials that look at harder clinical outcomes
like excessive bleeding events, FDA and virtually
all practitioners have used INR as a
surrogate outcome, she explained.
“Recent studies have showed poor patient
outcomes that we need to improve
upon,” Huang added, pointing to a 1,015patient
study by a research team led by
Brian Gage, MD, of Washington University
in St. Louis. The investigators found that
a dosing algorithm based on clinical factors
explained 17–22% of dose variability,
while another algorithm that incorporated
information about CYP2C9 and VKO-
RC1 explained 53–54% of dose variabil-
8 CliniCal laboratory news speCiaL eDiTion
mark linder
ity (Clinical Pharmacology
Therapeutics 2008 doi:
10.38/clpt.2008.10).
Huang also plans to
discuss data that support
expected cost effectiveness
of widespread testing. One
recent report estimates that
formally integrating genetic tests into routine
warfarin therapy could allow American
warfarin users to avoid between 4,500
and 22,000 serious bleeding events annually,
she pointed out (Personalized Medicine
2008; 5: 279–284).
Meanwhile, various studies also show
that particular variants of the CYP2C9 and
VKORC1 genes affect clearance and dose
requirements. “There’s a consistent relationship.
Even the worst critics of the test
acknowledge this consistent
and known relationship,”
added Mark Linder,
PhD, who is also speaking
in favor of more widespread
testing. Linder is
Amir Jaffer
Associate Director, Chemistry
and Toxicology and
Associate Director of the Pharmacogenetics
Diagnostic Laboratory at University of
Louisville Hospital in Louisville, Ky. and
Senior Vice President of PGXL Laboratories,
a private company that provides warfarin
testing services.
Wanted: Harder Outcomes
Noting that the expected benefits—improved
patient safety in the form of fewer
bleeding and clotting incidents—have been
detailed in various reports, opponents to
more widespread use of pharmacogenomic
warfarin testing are waiting for hard
evidence of these benefits. “There’s good
evidence that two SNPs on CYP2C9 and
several on VKORC1 affect warfarin metab-
Third annual
olympus partnership awards
presentation
Monday, july 28
1:30 p.m.–2:30 p.m.
ballroom abc of the
Walter e. Washington convention center
“How Healthy is the
Healthcare Debate on the
Campaign Trail and in the
Halls of Congress?”
Cokie Roberts, Political Analyst
for ABC News and National
Public Radio Senior News
Analyst, will share her thoughts
on this timely topic.
Underwritten by a grant from Olympus America.
paragon dx offers
Warfarin Genotyping
Whatever their stance on warfarin pharmacogenomic testing, visitors to
the Paragon Dx booth (3729) in the exhibit hall may learn their CYP2C9
and VKORC1 genotypes at no cost. While Paragon Dx recently received
FDA clearance for its Rapid Genotyping kit , the company also markets
ASR reagents for lab-developed tests and will be using them to genotype
meeting attendees onsite. According to Paragon Dx CEO Michael
Murphy, the company hopes to show lab directors that it’s possible to
run these warfarin pharmacogenomic tests in a space as small as the
company’s exhibit booth. While labs can genotype samples with Paragon
Dx reagents in 60 minutes, company representatives at the meeting
will be batching tests because they expect to do several hundred of
them.
olism. This we know well,” said Amir Jaffer,
MD, Associate Professor of Medicine at the
University of Miami’s Leonard M. Miller
School of Medicine and Service Chief of
Medicine at Miami Hospital. “What we
don’t know well is if testing translates into
evidence of improved clinical outcomes.”
Jaffer is speaking in opposition to more
widespread testing.
Both Jaffer and Charles Eby, MD, Associate
Professor in the Department of Pathology
and Immunology at Washington
University St. Louis School of Medicine,
Mo., want to see data that show warfarin
pharmacogenomic testing actually reduces
incidence of bleeding and mortality. Eby,
who will also speak against widespread
testing, considers such evidence the only
true measure of the tests’ worth. “Not a single
study shows a clinical benefit to testing,”
he pointed out.
While Huang maintained that a greater
percentage of time within the target therapeutic
target range and fewer patients with
INRs >4 are indeed clinical benefits, Eby
noted that only two trials that have used
therapeutic INR as endpoints were randomized
controlled studies. Those two
studies yielded conflicting results. The first
involved 206 patients and did not achieve
a reduction in out-of-range INRs (Circulation
2007;116: 2563–2570), but the other,
with 201 patients, found incorporating genetic
information into a dosing algorithm
increased patients’ time in a therapeutic
INR range (Clinical Pharmacology & Therapeutics
2008; 83: 460–470). However, these
studies’ control arms employed different
strategies for using genetic information for
warfarin dosing, Eby noted.
Other Considerations
Data aside, Eby raised concerns about how
labs should report genetic information and
how clinicians would use it. “Genetic information
by itself has minimal value unless
you put it into a dosing algorithm someone
can carry around in their head,” he explained,
“So should we provide an interpretation
by saying that a particular genotype
is associated with a decreased dose? Should
we provide an algorithm?”
Whatever labs report to physicians, “it’s
more than the usual accurate, precise results,”
Eby noted. While most hospital labs
have experience providing specific interpretive
comments for for certain tests, like
D-dimer, “we’ve never had to customize results
for each patient,” he pointed out. Eby
also worries about labs communicating
genetic information to an audience much
wider than the oncology subspecialties
that now receive it. Lab staff may be talk-
ing to clinicians who lack the education
and judgment to take into consideration
several other necessary factors— like age,
body mass, sex, and use of other drugs—
into dosing decisions, according to both
Eby and Jaffer.
Linder doesn’t share these fears. He
thinks opponents of wider testing are applying
a double standard to the issue. They
are worried about physicians learning to
use the test through a process of trial and
error, Linder said, but such processes are
inherent to the practice of medicine in
general and INR—the current standard of
care—in particular. “People are applying a
new set of rules to this test,” he said.
Jaffer also worries that genetic data
would be foisted upon physicians who are
unprepared to use it safely, responsibly, and
soon enough to yield benefits. One of his
concerns is that existing algorithms might
be too complicated for most physicians to
use in routine practice. “If we make dosing
more difficult, physicians might not start
therapy as soon. That would have a counter
effect on how patients do,” he asserted.
But complex algorithms are nothing
new, according to Huang. “Physicians adjust
dosage of drugs used in renal failure
with algorithms that are far more complicated,”
she maintained.
Linder disagrees with Jaffer’s expectation
that most physicians who prescribe
warfarin will use the pharmacogenomic
tests. “The test isn’t for all physicians, but
only those who understand it. It’s available
and useful now to those with specific
knowledge about how to use and interpret
it,” he explained.
Will Huang, Eby, Linder, and Jaffer sway
any opinions about warfarin pharmacogenomic
testing? The best way for meeting
attendees to find out is by attending what
promises to be an exciting debate. cln
Stop by the
AACC Booth
#3629
for the latest
information on all
our educational
programs.