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Sanofi US and Regeneron provided funding and suggested topics to
Cardiosource WorldNews. Drs. Bhatt and Shah received no payment
for their participation in this discussion.

ing low and working your way up to minimize
side effects and maximize tolerance. Is that a
strategy that you follow specifically in the outpatient setting? Or do you also do that if somebody
came in with an acute coronary syndrome (ACS)
in the inpatient setting?
Dr. Shah: This is mostly in an outpatient setting. I think post-ACS patients who may be a
little bit different, and the general trend there is
to initiate a high-dose statin, although deep down
I still feel that everybody does not need to be
on a high-dose statin routinely. I think we have
to individualize it. For example, if the baseline
pretreatment LDL-C level is 90 mg/dL and you
want to bring it down to 70 mg/dL maybe you
don’t need to start with a high dose statin. Maybe

what I just mentioned, would certainly raise the
suspicions for FH. For me, untreated LDL cholesterol levels generally in excess of 250 mg/dL
remains the predominant criterion, although, in
children, and in individuals under the age of 20,
anything in excess of 160 mg/dL might also trigger a search for heterozygous FH.
In our lab, we try to genotype everybody
whom we see. I have a big population of FH
patients whom I follow both in the lipid clinic, as
well as in the apheresis programs. As you know,
mutations in three major genes are responsible
for FH, and, of those three, the most common
mutation is in the LDL receptor gene, the second
most common one is in the Apo B100 gene, and
the third most common is in the PCSK9 gene.
One way to identify individuals who have not

“I wish I had a crystal ball. The potential for
any new treatment to change the paradigm is
great. I think we have to be cautious in not over
predicting what the future might hold.” —Dr. Shah

a lower or medium dose statin would be a good
initiating dose. So, with those caveats, generally higher dosage is used in the acute post-ACS
population in order to get their LDL-C closer to
the 50-70 mg/dL target.
Dr. Bhatt: What then are your thoughts about
diagnosing heterozygous familial hypercholesterolemia (HeFH)?
Dr. Shah: We have 13 or 14 million familial
hypercholesterolemics in the world—about a
little over half a million in the U.S. Nearly all FH
patients have heterozygous mutations, and a very
small fraction have homozygous mutations.
In diagnosing FH, we look for several things.
Firstly, we look for the individual to have family
history of premature coronary heart disease or
known FH in his or her first-degree relatives. Secondly, look at the pretreatment cholesterol level.
Generally, if the total cholesterol is over 300 mg/
dL and LDL cholesterol is over 250 mg/dL, that
would make us very suspicious that the patient
is likely to have heterozygous FH. Of course, if
they have LDL cholesterol levels over 600 mg/
dL, it’s more likely homozygous FH. So a positive
family history of either FH, a premature coronary
disease, or known cholesterol levels in excess of

been diagnosed is through genotyping of family members of someone with FH. You screen
the family members for a mutation—that’s the
concept of cascade screening. One of the most
important things that we should know about
heterozygous FH is that it’s grossly undiagnosed
and undertreated.
Dr. Bhatt: Let us say you find an heterozygous
FH patient, how would you treat that patient?
Dr. Shah: First of all, they don’t need any
further testing, especially for treatment evaluation, because the patient is by definition high
risk. Fifty percent of men with heterozygous FH
will have coronary heart disease (CHD) by age
50, and 30% of women with heterozygous FH
will have CHD by age 60. So they are already at
very high risk. So, again, a heart-healthy lifestyle
and modification of other risk factors is just as
important in these patients as it for routine CHD
patients.
And regarding cholesterol, LDL-C lowering
becomes a major target. Since their LDL-C levels
are very high, many of these patients will not
come within the goal of less than 100 mg/dL or
less than 70 mg/dL with the maximally tolerated
dose of a statin alone. In other words, you could

go for 40 mg or 80 mg of atorvastatin, and get
the LDL down by 50% or so. But if you start with
an LDL-C of 300 mg/dL LDL, you’re still down to
only 150 mg/dL. So the majority of these patients
will require additional help beyond statin therapy.
Until recently, after you had patients on maximum-tolerated treatment and their LDL-C was
still high, the only other viable option available
was LDL apheresis.
Dr. Bhatt: What do you think the impact of
emerging options 10 years down the road?
Dr. Shah: I wish I had a crystal ball. The potential for any new treatment to change the paradigm is great. I think we have to be cautious in
not over predicting what the future might hold. ■
Deepak L. Bhatt, MD, MPH, is Executive Director of
Interventional Cardiovascular Programs at Brigham
and Women’s Hospital Heart & Vascular Center and
Professor of Medicine at Harvard Medical School.
He is also a Senior Physician at Brigham and
Women’s Hospital and a Senior Investigator in the
TIMI Study Group.
Prediman K. Shah, MD, is the Director of the
Atherosclerosis Prevention and Treatment Center
and of the Oppenheimer Atherosclerosis Research
Center at Cedars-Sinai where he leads several
studies that focus on heart disease prevention and
treatment. Dr. Shah holds the Shapell and Webb
Family Chair in Clinical Cardiology at Cedars-Sinai
and is a Professor of Medicine and Cardiology. He is
the immediate past Director of Cardiology at Cedars
Sinai Heart Institute.
DISCLOSURE: Sanofi US and Regeneron provided funding
and suggested topics to Cardiosource WorldNews. Drs.
Bhatt and Shah received no payment for their participation
in this discussion.
Dr. Bhatt is on the executive committee of the Sanofi and
Regeneron ODYSSEY Outcomes trial. Dr. Shah has nothing
to disclose.
Conversations with Experts is a regularly occurring
educational feature of the ACC publication CardioSource
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trends in cardiovascular medicine.

©2015, Sanofi and Regeneron Pharmaceuticals, Inc. 10/2015 PCS-1177 US.ALI.15.10.033