Upload
stjosephsmedicalcenter
View
59
Download
0
Embed Size (px)
Citation preview
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
order to prevent 25 events, so the NNT is 83. 5 2011 CGHDI
● 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)
CHD: Unmet Clinical Needs Need for Detection of Unrecognized Risk
6 2010 CGHDI
(Lloyd-Jones et al. Arch Intern Med 2001;161:949-954)
2,498 M, 2,870 F
Bivariate ellipsoids show mean+2SD of total and HDL-cholesterol in Men
Solid line = with CHD
Broken line = without CHD
Framingham Heart Study, Total and HDL-Cholesterol and Prevalent CHD
Other Limitations of FRS
(Shah. JACC 2010;56:98-105)
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).
CV Events & Clinical Trials 20-30% RR Reduction is Not Enough
CD
P-N
A
SSSS
CA
RE
VA-H
IT
LIPI
D
LRC
-CPP
T
WO
S
OSL
O
AFC
APS
/TEX
Hel
sink
i
0
10
20
30
40
50
60
70
% w
ith C
V Ev
ent
% CONTROL GROUP
% TREATMENT GROUP17%
33%24%
46% 33%
17%31%
37%
24%22%
% Clinical Events in Large Trials Control vs. Treatment Groups
Many patients reduce LDLC yet Continue to have Events !
(Superko HR. Beyond LDL-C, Circ. 1996;94:2351-2354) (Superko & King. 2008;117:560-568)
Control group with events
Treatment group with events
Chol Lowering Worked
Chol Lowering Did NOT Work 2008 CGHDI
Agenda 1. Is there a Need for Genetic CVD Testing?
2. Can Gene Tests Improve on what we already have?
Risk determination – 9p21, 4q25
Side Effect Evaluation – SLCO1B1
Treatment Decision
Compliance – AKROBATS
1. Genetics and noninvasive Imaging
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
Per allele summary OR: 1.27 (1.24-1.31), p = 10-60
Attributable fraction 22% Schunkert H, et al. Circulation 2008; 117:1675
P=0.000000000000000000000000000000000000000000000000000000000001
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%)
5-10% 6.0% 86.8% 7.2% 0 328 (13.2%)
10-20% 0 8.6% 86.5% 4.9% 292 (13.5%)
> 20% 0 0 12.3% 87.7% 66 (10.5%)
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).
NRI
26.7%
Or
39.5%
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%)
5-10% 6.8% 87.9% 5.3% 0 334 (12.1%)
10-20% 0 8.0 87.4% 4.6% 251 (12.6%)
> 20% 0 0 10.5% 89.5% 66 (10.5%)
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).
NRI
24.7%
Or
38.6%
2011 CGHDI
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?
Atrial Fibrillation – 4q25
• ~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
4q25 rs2200733 is Associated with AF and CE Stroke
Atrial Fibrillation Cardioembolic Stroke
8. Shi, et al. Hum Genet. 2009;126:843 9. Body, et al. Circ Cardiovasc Genet. 2009;2:4910. Virani, et al. Am J Cardiol. 2011;107:1504 11. Husser, et al. JACC. 2010;55:747 12. Gretarsdottir, et al. Ann Neuro. 2008;64:402 13. Wnuk, et al. Neuro Neorochir Pol. 2011;45:148 14. Celera and Collaborators, to submit 2Q2012
1. Gudbjartsson, et al. Nature Genetics. 2007;41:876 2. Kaab, et al. Eur Heart J. 2009;30:87913 3. Kiliszek, et al. PLoS ONE. 2011;6:e21790 4. Anselmi, et al. Heart. 2008;94:1394 5. Lubitz et, al. Circ. 2010;122:976 6. Schnabel, et al. Circ Cardiovasc Genet. 2011;4:557 7. Gbadebo, et al. Am Heart J. 2011;162:31
a. Per copy of the risk allele in additive models b. Recurrent AF was not included
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
1. Gudbjartsson, et al. Nature. 2007;48:353 2. Kaab et al. Eur Heart J. 2009;30:813 3. Kiliszek, et al. PLoS ONE. 2011;6:e21790 4. Lubitz, et al. Circ. 2010;122:976
Atrial Fibrillation
5. Gretarsdottir, et al. Ann Neuro. 2008;64:402 6. Lemmens, et al.Stroke. 2010;41:00 7. Celera and collaborators to submit 2Q2012
a. Per copy of the risk allele in additive models
Cardioembolic Stroke
Target Populations and Possible Clinical Utility Help to Prevent or Reverse the Progression of AF
• “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”
20
Sinner, et al. Cardiovasc Res. 2011;89:701
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
Target Populations and Possible Clinical Utility Help to Prevent Recurrent Stroke Related to AF
21
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
Damani and Topel. Genome Medicine. 2009;1:54 Connelly, et al. N Eng J Med. 2009;361:1139
Granger, et al. N Eng J Med. 2011;365:981 Patel, et al. N Eng J Med. 2011;365:883
Or newer anti-coagulants with lower bleeding risk and easier dosing, e.g. dabigatran, apixaban, and rivaroxaban
Agenda 1. Is there a Need for Genetic CVD Testing?
2. Can Gene Tests Improve on what we already have?
Risk determination – 9p21, 4q25
Side Effect Evaluation – SLCO1B1
Treatment Decision
Compliance – AKROBATS
3. Genetics and noninvasive Imaging
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?
News & EventsHome > News & Events > Newsroom > Press AnnouncementsFDA NEWS
RELEASEFor Immediate Release: June 8, 2011Media Inquiries: Morgan Liscinsky, 301-
796-0397, [email protected] 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.
FDA U.S. Food and Drug Administration June 8, 2011
http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm258384.htm
SLCO1B1 Variants and Statin-Induced Myopathy - A Genome-Wide Study
N Engl J Med, 359(8):789-799, August 21, 2008
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
26
Cumulative Risk of Myopathy Associated with Simvastatin According to SLCO1B1 Genotype
The SEARCH Collaborative Group. N Engl J Med 2008;359:789-799
Conclusion:
We have identified common variants in SLCO1B1 that are strongly associated with an increased risk of statin-induced myopathy
•Genotyping these variants may help to achieve the benefits of statin therapy more safely and effectively
Cumulative % of Pts who had a myopathy
20%
Years on 80 Simvastatin
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 1. Is there a Need for Genetic CVD Testing?
2. Can Gene Tests Improve on what we already have?
Risk determination – 9p21, 4q25
Side Effect Evaluation – SLCO1B1
Treatment Decision - LPA
Compliance – AKROBATS
3. Genetics and noninvasive Imaging
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.”
30
The Ile4399Met Variant of the LPA Gene
● 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
Ile4399Met (rs3798220)
Variable number of kringle repeats
TG
FC CE
PL
0.5 1.0 2.0 4.0 7.0
● 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
Smoking Diabetes
HDL-Cholesterol†
Total Cholesterol‡
Hypertension§
§ 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
The Risk Associated with LPA Variant Comparable to Traditional Risk Factors
Hazard Ratio
rs3798220 (C)
Risk of Carrying 4399Met Comparable to Known RFs
1.0
1.5
2.0
2.5
Risk
Rat
io S
cale
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 4. Chasman et al., Atherosclerosis 2009;203:371
The magnitude of risk associated with carrying LPA 4399Met is comparable to those associated with known traditional risk factors
2011 CGHDI
LPA 4399Met and Aspirin in WHS Effect of Aspirin Treatment
Heterozygotes, placebo
Noncarriers
Heterozygotes, aspirin
Frac
tion
with
Maj
or C
VD
*
*Major CVD = MI, stroke, or cardiovascular death
*
• 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
Pinteraction = 0.048
(SNP by aspirin therapy)
Chasman et al. Atherosclerosis 2009; 203:371
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
Agenda 1. Is there a Need for Genetic CVD Testing?
2. Can Gene Tests Improve on what we already have?
Risk determination – 9p21, 4q25
Side Effect Evaluation – SLCO1B1
Treatment Decision - LPA
Compliance – AKROBATS
3. Genetics and noninvasive Imaging
4. Families
2012 CGHDI
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
(DeBusk R, Miller N, Superko H, et al. Annals of Int Med 1994;120:721-729) 2007 CGHDI
Compliance to Medications
6 mo 12 mo
MD 17% 21%
RN 98% 90%
Can a Genetic Test Improve Compliance?
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
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
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.
Noninvasive Imaging for Coronary Calcium
9p21 and Coronary Artery Calcification
(rs10757278)
(Assimes T et al Human Molec Genetics 2008:17:2320-2328)
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.
SHAPE II Genetic Tests and Noninvasive Imaging Tests
(Current Athero Reports 2011;epub Aug 10)
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.”
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
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.
45
Case: 2011-09
MI 57yr 9p21++
35 yr 9p21+
7 yr 5 yr
CAC? Work-up?
Statin Statin+NA = 9p21 Homozygous
(Copyright by CGHDI 2011)
33 yr 9p21+
= 9p21 Heterozygous
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.