Dr.Superko_GeneticTesting_SJMC Cardiovascular Symposium

Saint Joseph’s Medical Center Cardiac Symposium
Saturday, February 9, 2013

Genetic Testing: How It All Fits
into Clinical Practice

H. Robert Superko, MD, FACC, FAHA, FAACVPR
Chief Medical Officer - Celera
Clinical Professor - Mercer University School of Pharmaceutical Sciences
Chairman - Cholesterol, Genetics, and Heart Disease Institute (501C3)
Prevention Committee, St. Joseph’s Hospital - Atlanta

 2013 CGHDI

Disclosures
Chief Medical Officer – Celera/BHL/Quest
CV Prevention Committee, Saint Joseph’s Hospital Atlanta
Director, Cholesterol, Genetics, and Heart Disease
Institute (501C3 non-profit)
Clinical Professor - Mercer University School of
Pharmaceutical Sciences
Pharmaceutical Company Lectures – None
Pharmaceutical Company Consulting - None

 2010 CGHDI

In order to have Practical Clinical Utility, a new
test should CHANGE what we routinely do and:

Alter the DIAGNOSIS or Risk Categorization

Alter TREATMENT Decisions

Alter COMPLIANCE

Alter OUTCOMES

Agenda

1. Is there a Need for Genetic CVD Testing?
2. Can Gene Tests Improve on what we
already have?
3. Genetics and noninvasive Imaging
4. Families

 2011 CGHDI

RRR, ARR and NNT
• Relative Risk Reduction (RRR) assesses the reduction in risk in one group
relative to another group such as the risk reduction noted in the
treatment group compared to the placebo group. For example, if the total
study size is 2,000 placebo and 2,000 treatment subjects, and 100 placebo
patients have an event (5%) relative to 75 events in the treatment group
(3.8%), the RRR is 25% (25/100).
• Absolute Risk Reduction (ARR) assesses the absolute reduction difference
in risk in one group compared to the absolute reduction in another group.
In the example above, the ARR would be 1.2% (5.0%-3.8%).
• Number Needed to Treat (NNT) is a method that can assess the efficiency
of different therapies. NNT is the number of subjects that are needed to
be treated in order to prevent one event in a defined time period and is
the inverse of the ARR. In general, the higher the NNT the less efficient,
and the lower the NNT, the greater the efficiency of the treatment. For
example, in the example above, it was necessary to treat 2,000 subjects in
5  2011 CGHDI
order to prevent 25 events, so the NNT is 83.

CHD: Unmet Clinical Needs
Need for Detection of Unrecognized Risk

● A majority of middle-age patients who experienced a first myocardial
infarction (MI) had a traditional risk factor profile which would not
have qualified them for preventive medical therapy. Akosah et al
JACC (2003)

● “Although current risk estimates work very effectively in populations,
variation of estimated risk leads to misclassification of true risk in
individual patients.” Berman et al JACC (2004)

● “…even risk algorithms based on established risk factors are limited
in predictive power for individuals. More effective prediction tools are
needed.” Grundy et al Circulation (2006)

6  2010 CGHDI

Framingham Heart Study, Total and HDL-Cholesterol and Prevalent CHD

2,498 M, 2,870 F
Bivariate ellipsoids show mean+2SD of total
and HDL-cholesterol in Men
Solid line = with CHD
(Lloyd-Jones et al. Arch Intern Med 2001;161:949-954)
Broken line = without CHD

Other Limitations of FRS
Substantial underestimation of lifetime risk, especially in women.

75% of patients (men < 55 yrs and women < 65 yrs) with a first MI would have
been considered ineligible for a statin use under current NCEP guidelines
(Akosah, et al)

FRS does not incorporate family history and some components of the Meta
Syn.

60-70% of unheralded CV events occur in: “low” and “intermediate” risk
categories (Need for Reclassification).

(Shah. JACC 2010;56:98-105)

CV Events & Clinical Trials
20-30% RR Reduction is Not Enough
70 % CONTROL GROUP
% Clinical 60 17% % TREATMENT GROUP
Events in
Large Trials 50 33%
% with CV Event

Many patients
24% Chol Lowering Worked reduce LDLC yet
Control vs. 40 24% Continue to have
Treatment 22% 17% Events !
30
Groups 31%
20 46% 37% 33%

10
Control group
with events 0

WOS
LIPID

OSLO
VA-HIT
SSSS

CARE
CDP-NA

Helsinki
LRC-CPPT
Treatment group

AFCAPS/TEX
with events
Chol Lowering Did NOT Work
(Superko HR. Beyond LDL-C, Circ. 1996;94:2351-2354)  2008 CGHDI
(Superko & King. 2008;117:560-568)

Agenda
already have?
Risk determination – 9p21, 4q25
Side Effect Evaluation – SLCO1B1
Treatment Decision
Compliance – AKROBATS
4. Families
 2011 CGHDI

Problem: Standard CVD Risk Evaluation can
misidentify large segments of the population.

Question: Can 9p21 information improve risk
detection?

More 9p21.3 confirmation
largest meta-analysis to date

P=0.00000000000000000000000000000000
0000000000000000000000000001

Per allele summary OR: 1.27 (1.24-1.31), p = 10-60
Attributable fraction 22% Schunkert H, et al. Circulation 2008; 117:1675

9p21 Risk Reclassification in FRS (Brautbar A et al Circ CV Genet 2009;2:279-285)
Improved Risk Assessment
N = 9,998, 14.6 yr follow-up
Total
10 yr Risk 0-5% 5-10% 10-20% >20% Reclassified
0-5% 97.7% 2.3% 0 0 110 (2.3%) NRI
5-10% 6.0% 86.8% 7.2% 0 328 (13.2%) 26.7%

10-20% 0 8.6% 86.5% 4.9% 292 (13.5%) Or

> 20% 0 0 12.3% 87.7% 66 (10.5%) 39.5%

N 4,648 2,746 1,953 651
• 17.1% of intermediate-low and 15.8% of intermediate-high FRS participants were
reclassified, with potential changes in clinical management.
• Almost 90% of men and women in the two intermediate-risk categories had LDL-C levels of
100 mg/dL or higher (~ 55%-66% had levels > 130 mg/dL).

 2011 CGHDI

9p21 Risk Reclassification in ARIC (Brautbar A et al Circ CV Genet 2009;2:279-285)
Improved Risk Assessment
N = 9,998, 14.6 yr follow-up
Total
10 yr Risk 0-5% 5-10% 10-20% >20% Reclassified
0-5% 96.6% 3.4% 0 0 157 (3.4%) NRI
5-10% 6.8% 87.9% 5.3% 0 334 (12.1%) 24.7%

10-20% 0 8.0 87.4% 4.6% 251 (12.6%) Or
> 20% 0 0 10.5% 89.5% 66 (10.5%) 38.6%
N 4,648 2.746 1,953 651
• 17.1% of intermediate-low and 15.8% of intermediate-high FRS participants were
reclassified, with potential changes in clinical management.
• Almost 90% of men and women in the two intermediate-risk categories had LDL-C levels of
100 mg/dL or higher (~ 55%-66% had levels > 130 mg/dL).

 2011 CGHDI

Atrial Fibrillation – 4q25

Problem: A Fib affects 2.2 million Americans and
probably the same number with undiagnosed AF. It
is the most common cause of cardioembolic stroke.
Annual costs ~ $7 Billion

Question: Can AF risk be predicted and would it
improve clinical decisions and/or outcomes?

4q25 rs2200733 is Associated with AF and CE Stroke
• ~1.7 fold increased risk for AF and ~1.5 fold for CE stroke per risk allele
• The genotypes of rs2200733 and rs10033464 are not correlated (r2=0.01)
• At least one copy of the rs2200733 risk allele is carried by ~21% of
Caucasians,70% of Asians, 40% of African Americans, and 50% of Hispanics
• The closest gene, PITX2, encodes a protein that is critical for determining left-
right asymmetry, sinoatrial (SA) node formation, and the differentiation of the
left atrium
Atrial Fibrillation Cardioembolic Stroke

1. Gudbjartsson, et al. Nature Genetics. 2007;41:876 8. Shi, et al. Hum Genet. 2009;126:843
2. Kaab, et al. Eur Heart J. 2009;30:87913 9. Body, et al. Circ Cardiovasc Genet. 2009;2:49
3. Kiliszek, et al. PLoS ONE. 2011;6:e21790 10. Virani, et al. Am J Cardiol. 2011;107:1504
4. Anselmi, et al. Heart. 2008;94:1394 11. Husser, et al. JACC. 2010;55:747
5. Lubitz et, al. Circ. 2010;122:976 12. Gretarsdottir, et al. Ann Neuro. 2008;64:402
a. Per copy of the risk allele in additive models 6. Schnabel, et al. Circ Cardiovasc Genet. 2011;4:55713. Wnuk, et al. Neuro Neorochir Pol. 2011;45:148
b. Recurrent AF was not included 7. Gbadebo, et al. Am Heart J. 2011;162:31 14. Celera and Collaborators, to submit 2Q2012

4q25 rs10033464 is Associated with AF and CE Stroke
• ~ 1.4 fold increased risk of AF and ~1.3 fold increased risk of CE stroke in
Caucasians
• At least one copy of the rs10033464 risk allele is carried by ~18% of Caucasians,
38% of Asians, 42% of Af. Americans, and 25% of Hispanics
• This risk is independent of the rs2200733 risk allele
Atrial Fibrillation Cardioembolic Stroke

a. Per copy of the risk allele in additive models 1. Gudbjartsson, et al. Nature. 2007;48:353 Gretarsdottir, et al. Ann Neuro. 2008;64:402
5.
2. Kaab et al. Eur Heart J. 2009;30:813 6. Lemmens, et al.Stroke. 2010;41:00
3. Kiliszek, et al. PLoS ONE. 2011;6:e21790 Celera and collaborators to submit 2Q2012
7.
4. Lubitz, et al. Circ. 2010;122:976

Target Populations and Possible Clinical Utility
Help to Prevent or Reverse the Progression of AF
Target Population: patients having a single episode or a history of AF and no longer in
AF or a history suspicious for AF
4q25 Carriers: trigger early AF monitoring and treatment to help prevent or reverse
AF progression

• “Current… treatments for AF are
initiated after the onset of the
arrhythmia and in many cases after
sustained periods of AF”

• “Ultimately, genetic information may
be useful in identifying high-risk
patients;… an early, genotype-guided
treatment might thus help to prevent
or ameliorate progression of AF”

Sinner, et al. Cardiovasc Res. 2011;89:701
20

Target Populations and Possible Clinical Utility
Help to Prevent Recurrent Stroke Related to AF
Target Population: stroke patients without a diagnosis of AF

4q25 Carriers: aid decision for the likelihood of occult AF, help prevent recurrent
stroke due to undetected AF, and help with antithrombotic
treatment decisions

Or newer anti-coagulants with
lower bleeding risk and easier
dosing, e.g. dabigatran,
apixaban, and rivaroxaban
Damani and Topel. Genome Medicine. 2009;1:54 Granger, et al. N Eng J Med. 2011;365:981
Connelly, et al. N Eng J Med. 2009;361:1139 Patel, et al. N Eng J Med. 2011;365:883
21

Agenda
already have?
Treatment Decision
4. Families
 2012 CGHDI

Problem: In the ‘Real World’ statins appear to create
adverse side effects that compromise adherence.

Question: Can a gene test help to identify statin intolerant
individuals and/or help explain adverse side effects that
impact complaince?

FDA U.S. Food and Drug Administration June 8, 2011

News & EventsHome > News & Events > Newsroom > Press AnnouncementsFDA NEWS
RELEASEFor Immediate Release: June 8, 2011 Media Inquiries: Morgan Liscinsky, 301-
796-0397, morgan.liscinsky@fda.hhs.gov Consumer Inquiries: 888-INFO-FDAFDA
announces new safety recommendations for high-dose simvastatin
 Increased risk of muscle injury citedThe U.S. Food and Drug Administration today is
announcing safety label changes for the cholesterol-lowering medication simvastatin
because the highest approved dose--80 milligram (mg)--has been associated with an
elevated risk of muscle injury or myopathy, particularly during the first 12 months of
use.
The risk of muscle injury is highest during the first year of treatment with the 80 mg
dose of simvastatin, is often the result of interactions with certain other medicines, and
is frequently associated with a genetic predisposition for simvastatin-related muscle
injury.
http://www.fda.gov/Safety/MedWatch/SafetyInformation/Safety
AlertsforHumanMedicalProducts/ucm258384.htm

SLCO1B1 Variants and Statin-Induced Myopathy - A
Genome-Wide Study

A genome-wide screen of patients with myopathy who were
taking high-dose simvastatin (80 mg per day) showed a strong
association between myopathy and variants of SLCO1B1, which
encodes an organic anion-transporting polypeptide
Approximately 60% of the cases of myopathy could be
attributed to these variants
The association was replicated in an independent study

Genotyping SLCO1B1 variants may be helpful for tailoring the
dosage of statins and safety monitoring

N Engl J Med, 359(8):789-799, August 21, 2008

Cumulative Risk of Myopathy Associated with Simvastatin
According to SLCO1B1 Genotype

Conclusion:
20%
We have identified common
variants in SLCO1B1 that are
strongly associated with an
Cumulativ increased risk of statin-
e % of Pts induced myopathy
who had a •Genotyping these variants
myopathy may help to achieve the
benefits of statin therapy
more safely and effectively

Years on 80 Simvastatin

26 The SEARCH Collaborative Group. N Engl
J Med 2008;359:789-799

STRENGTH
(Statin Response Examined by Genetic Haplotype Markers)
N = 509 randomized to atorva 10 then 80mg/d, simva 20 then 80, prava 10 then 40.
Composite Adverse Events (CAE) = discontinuation for any SE, myalgia, CK > 3X ULN
SLCO1B1*5 (rs4149056) present in 28% of entire cohort:
CAE = 35% no-CAE = 25% (p=0.03) 62% developed CAE in first 8 wks
Gene Dose Effect for CAE:
0 allele = 19%, 1 allele = 27%, 2 alleles = 50% (p=0.01)
Female CAE > Male CAE:
% Female CAE = 66% vs % female no-CAE = 50% (p=0.01)
Consistent across statin type
CONCLUSIONS:
SLCO1B1*5 carriers at 2-fold increase risk for statin induced side effects even with
normal CK levels.
CAE with SLCO1B1*5 seen with Simva and Atorva but not Prava
“Our findings suggest that pravastatin, instead of simvastatin, may be a reasonable first
choice statin for carriers of the SLCO1B1*5 allele, wheras women may benefit from
increased surveillance for symptoms.”
(Voora D et al. JACC 2009;54:1609-1616)

Agenda
already have?
Treatment Decision - LPA
4. Families
 2012 CGHDI

Harvard Heart Letter
Vol 20. Number 6. February 2010
“Do healthy people need an aspirin a day?”

Finding the Tipping Point
“Don’t take aspirin just because you’ve heard it can help
prevent a heart attack or stroke. It can, but it can also do
some damage.”

“It isn’t the easiest decision to make. If you are in the
gray zone, talking with your doctor could make it more
black and white.”

The Ile4399Met Variant of the LPA Gene
PL
T F
G C
C
E

Variable number of
kringle repeats

Ile4399Met
(rs3798220)

● LPA gene encodes the apo(a) component of Lp(a)
● High plasma levels of Lp(a) are associated with cardiovascular disease
● The Ile4399Met variant is located in the protease-like domain of apo(a)
Image: Albers, Koschinsky & Marcovina. Kidney International 2007; 71:961
30

The Risk Associated with LPA Variant
Comparable to Traditional Risk Factors

Smoking
Diabetes
Hypertension§
rs3798220 (C)
HDL-Cholesterol†
Total Cholesterol‡
0.5 1.0 2.0 4.0 7.0

Hazard Ratio

● Risk among carriers of the rs3798220 C (Met) allele is for the primary end point of
WHS (MI, ischemic stroke, or CV death)
● Adjusted for age, blood pressure, history of diabetes, smoking status, family history
of MI, LDL-C, and HDL-C
● Risk for traditional risk factors (adjusted for each other and age) is estimated from
white women in ARIC
§ Stage II-IV (SBP≥160, DBP≥100) vs. Normal (SBP<130, DBP<85)
†< 35 vs. 50-59 mg/dL
‡ 240-279 vs. 160-199 mg/dL

Risk of Carrying 4399Met Comparable to Known RFs

2.5

Risk Ratio Scale 2.0

1.5

1.0

The magnitude of risk associated with carrying LPA 4399Met is
comparable to those associated with known traditional risk factors
1. Di Angelantonio et al.,JAMA 2009;302:993
2. Sesso HD et al., Hypertension 2000;36:801
3. Schaefer et al., JAMA 1994;271:999
 2011 CGHDI
4. Chasman et al., Atherosclerosis 2009;203:371

LPA 4399Met and Aspirin in WHS
Effect of Aspirin Treatment

*

Heterozygotes, placebo

Fraction with Major CVD*
Pinteraction = 0.048 Noncarriers
(SNP by aspirin therapy)

Heterozygotes, aspirin

• 3.5% of European Americans were carriers of the LPA SNP
• Risk for CHD is increased by >2 fold for carriers compared with noncarriers
• In WHS, this excess risk is ameliorated by low-dose aspirin treatment
*Major CVD = MI, stroke, or cardiovascular death Chasman et al. Atherosclerosis 2009; 203:371

2009 US Preventive Services Task Force Guidelines
Estimated Benefits and Harms

Clinical Utility for LPA Testing

• USPSTF aspirin use guidelines recommend considering information about CVD risk and bleeding risk in
assessing the risk:benefit ratio of aspirin use

• Men and women who carry the LPA variant have ~2-fold higher risk of CVD

• For LPA carriers, 5 events are prevented by low-dose aspirin treatment for every 1 major bleed caused

• Number Needed to Treat (NNT) for prevention of major CVD events with aspirin in WHS

– 37 in carriers
– 625 in noncarriers
• In WHS, aspirin use caused ~ 15 fold more bleeds for each CVD event prevented in noncarriers than in
carriers

• LPA testing can help identify patients for whom aspirin has an appropriate risk:benefit ratio

NHLBI - Multifit Trial - 1988
Hypothesis: RN management of lipid disorders is more successful
than MD management.
Setting: Stanford University & 5 Kaiser Permanente Hospitals.
585 men & women with acute MI. 1988-1991
Protocol: Randomized to MD or RN management for 1 year.
RN’s followed 4 specific lipid treatment algorithms

Compliance to Medications
6 mo 12 mo Can a Genetic Test
Improve Compliance?
MD 17% 21%

RN 98% 90%
 2007 (DeBusk R, Miller N, Superko H, et al. Annals of Int Med 1994;120:721-729)
CGHDI

Patient Knowledge of pharmacogenetic
information improves adherence to statin
therapy: Results of the Additional KIF6 Risk
Offers Better Adherence to Statins
(AKROBATS) Trial

Scott Charland et al.
ACC Abstract # 1258-376
Monday March 26, 2012 ACC
Moderated Poster – South Hall A

Noninvasive Imaging for Coronary Calcium

Problem:
50% of individuals are FIRST diagnosed with CHD with SUDDEN DEATH.

67% of out-of-hospital EMS treated cardiac arrests have no symptoms
within one hour of death .

Subclinical atherosclerosis (CAC) increases CHD event risk significantly.

Should everyone be screened with Fast CT for coronary calcium?

Solution:
Utilize genetic risk markers to identify individuals at higher risk and
recommend CAC screening in high risk subgroup.

9p21 and Coronary Artery Calcification
(rs10757278)

CARDIA and ADVANCE studies
Group OR p
Caucasian 1.37 0.0018
African Am 1.18 0.61
Hispanic 1.61 0.20
East Asian 1.58 0.17

Majority of cases were Caucasian, limited numbers of other ethnic groups.

(Assimes T et al Human Molec Genetics 2008:17:2320-2328)

SHAPE II Genetic Tests and Noninvasive Imaging Tests

Conclusion:

“Since family history is such a powerful predictor of CHD events, the
combination of simple and relatively inexpensive genetic tests to clarify
risk, followed by noninvasive imaging in the high risk population, allows
identification of a group most deserving of aggressive and individualized
treatment.”
(Current Athero Reports 2011;epub Aug 10)

Premature CAD & 9p21
“Entire families sometimes show this tendency to early
arteriosclerosis. A tendency which cannot be explained in any other
way than that in the make-up of the machine bad material was
used for the tubing.”

(William Osler. The Principles and Practice of Medicine. D.
Appleton & Co. New York, 1892; Pg 664)

With advances in our understanding of genetic influences on
CHD risk, the time has come to apply this knowledge in routine
clinical practice in order to improve patient care. Indeed, in
may be past time. In 1989 Karl Berg wrote “Knowledge of
genetic factors in the etiology of coronary heart disease has not
so far been adequately utilized in attempts to combat
premature CHD. The time has now come to utilize genetic
information in a setting of family-oriented preventive
medicine.

Case: 2011-09

MI 57yr
9p21++

35 yr
9p21+

33 yr
9p21+
CAC?
Work-up?
Statin 7 yr 5 yr
Statin+NA = 9p21 Homozygous

= 9p21 Heterozygous
45
(Copyright by CGHDI 2011)

What’s New: Buccal Swabs

(Clin Card 2010;33:E1-E6)

Conclusions
1. CHD is in large part a Gene / Environment Disease
2. Genetic tests exist that help to more accurately identify risk in
primary and secondary prevention.
3. Genetic tests assist our current clinical decision making
process.
4. Genetic tests may be beneficial in identifying high risk groups
that may benefit the most from additional testing (test yield)
5. Genetic tests may be helpful in family heart disease
assessment.
6. Genetic tests may help compliance.

Dr.Superko_GeneticTesting_SJMC Cardiovascular Symposium

Recommended

Recommended

More Related Content

What's hot

What's hot (19)

Similar to Dr.Superko_GeneticTesting_SJMC Cardiovascular Symposium

Similar to Dr.Superko_GeneticTesting_SJMC Cardiovascular Symposium (20)

Dr.Superko_GeneticTesting_SJMC Cardiovascular Symposium