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Dr.Superko_GeneticTesting_SJMC Cardiovascular Symposium
 

Dr.Superko_GeneticTesting_SJMC Cardiovascular Symposium

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    Dr.Superko_GeneticTesting_SJMC Cardiovascular Symposium Dr.Superko_GeneticTesting_SJMC Cardiovascular Symposium Presentation Transcript

    • 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 - CeleraClinical Professor - Mercer University School of Pharmaceutical Sciences Chairman - Cholesterol, Genetics, and Heart Disease Institute (501C3) Prevention Committee, St. Joseph’s Hospital - Atlanta  2013 CGHDI
    • DisclosuresChief Medical Officer – Celera/BHL/QuestCV Prevention Committee, Saint Joseph’s Hospital AtlantaDirector, Cholesterol, Genetics, and Heart DiseaseInstitute (501C3 non-profit)Clinical Professor - Mercer University School ofPharmaceutical SciencesPharmaceutical Company Lectures – NonePharmaceutical Company Consulting - None  2010 CGHDI
    • In order to have Practical Clinical Utility, a newtest should CHANGE what we routinely do and:Alter the DIAGNOSIS or Risk CategorizationAlter TREATMENT DecisionsAlter COMPLIANCEAlter OUTCOMES
    • Agenda1. Is there a Need for Genetic CVD Testing?2. Can Gene Tests Improve on what we already have?3. Genetics and noninvasive Imaging4. 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 NeedsNeed 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 CHD2,498 M, 2,870 FBivariate ellipsoids show mean+2SD of totaland HDL-cholesterol in MenSolid line = with CHD (Lloyd-Jones et al. Arch Intern Med 2001;161:949-954)Broken line = without CHD
    • Other Limitations of FRSSubstantial underestimation of lifetime risk, especially in women.75% of patients (men < 55 yrs and women < 65 yrs) with a first MI would havebeen considered ineligible for a statin use under current NCEP guidelines(Akosah, et al)FRS does not incorporate family history and some components of the MetaSyn.60-70% of unheralded CV events occur in: “low” and “intermediate” riskcategories (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)
    • Agenda1. 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 – AKROBATS1. Genetics and noninvasive Imaging4. Families  2011 CGHDI
    • Problem: Standard CVD Risk Evaluation canmisidentify large segments of the population.Question: Can 9p21 information improve riskdetection?
    • More 9p21.3 confirmation largest meta-analysis to date P=0.00000000000000000000000000000000 0000000000000000000000000001Per 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 – 4q25Problem: A Fib affects 2.2 million Americans andprobably the same number with undiagnosed AF. Itis the most common cause of cardioembolic stroke.Annual costs ~ $7 BillionQuestion: Can AF risk be predicted and would itimprove 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 rivaroxabanDamani and Topel. Genome Medicine. 2009;1:54 Granger, et al. N Eng J Med. 2011;365:981Connelly, et al. N Eng J Med. 2009;361:1139 Patel, et al. N Eng J Med. 2011;365:883 21
    • Agenda1. 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 – AKROBATS3. Genetics and noninvasive Imaging4. Families  2012 CGHDI
    • Problem: In the ‘Real World’ statins appear to createadverse side effects that compromise adherence.Question: Can a gene test help to identify statin intolerantindividuals and/or help explain adverse side effects thatimpact complaince?
    • FDA U.S. Food and Drug Administration June 8, 2011News & EventsHome > News & Events > Newsroom > Press AnnouncementsFDA NEWSRELEASEFor Immediate Release: June 8, 2011
Media Inquiries: Morgan Liscinsky, 301-796-0397, morgan.liscinsky@fda.hhs.gov
Consumer Inquiries: 888-INFO-FDAFDAannounces new safety recommendations for high-dose simvastatin
Increased risk of muscle injury citedThe U.S. Food and Drug Administration today isannouncing safety label changes for the cholesterol-lowering medication simvastatinbecause the highest approved dose--80 milligram (mg)--has been associated with anelevated risk of muscle injury or myopathy, particularly during the first 12 months ofuse.The risk of muscle injury is highest during the first year of treatment with the 80 mgdose of simvastatin, is often the result of interactions with certain other medicines, andis frequently associated with a genetic predisposition for simvastatin-related muscleinjury. http://www.fda.gov/Safety/MedWatch/SafetyInformation/Safety AlertsforHumanMedicalProducts/ucm258384.htm
    • SLCO1B1 Variants and Statin-Induced Myopathy - A Genome-Wide StudyA genome-wide screen of patients with myopathy who weretaking high-dose simvastatin (80 mg per day) showed a strongassociation between myopathy and variants of SLCO1B1, whichencodes an organic anion-transporting polypeptideApproximately 60% of the cases of myopathy could beattributed to these variantsThe association was replicated in an independent studyGenotyping SLCO1B1 variants may be helpful for tailoring thedosage of statins and safety monitoring N Engl J Med, 359(8):789-799, August 21, 2008
    • Cumulative Risk of Myopathy Associated with SimvastatinAccording to SLCO1B1 Genotype Conclusion: 20% We have identified common variants in SLCO1B1 that are strongly associated with anCumulativ increased risk of statin-e % of Pts induced myopathywho had a •Genotyping these variantsmyopathy 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 ULNSLCO1B1*5 (rs4149056) present in 28% of entire cohort: CAE = 35% no-CAE = 25% (p=0.03) 62% developed CAE in first 8 wksGene 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 typeCONCLUSIONS:SLCO1B1*5 carriers at 2-fold increase risk for statin induced side effects even withnormal 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 firstchoice statin for carriers of the SLCO1B1*5 allele, wheras women may benefit fromincreased surveillance for symptoms.” (Voora D et al. JACC 2009;54:1609-1616)
    • Agenda1. 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 – AKROBATS3. Genetics and noninvasive Imaging4. 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 helpprevent a heart attack or stroke. It can, but it can also dosome damage.”“It isn’t the easiest decision to make. If you are in thegray zone, talking with your doctor could make it moreblack and white.”
    • The Ile4399Met Variant of the LPA Gene PL T F G C C EVariable number ofkringle 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 GuidelinesEstimated 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
    • Agenda1. 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 – AKROBATS3. Genetics and noninvasive Imaging4. 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 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 statintherapy: 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
    • Agenda1. Is there a Need for Genetic CVD Testing?2. Can Gene Tests Improve on what we already have?3. Genetics and noninvasive Imaging4. Families  2011 CGHDI
    • Noninvasive Imaging for Coronary CalciumProblem:50% of individuals are FIRST diagnosed with CHD with SUDDEN DEATH.67% of out-of-hospital EMS treated cardiac arrests have no symptomswithin 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 andrecommend CAC screening in high risk subgroup.
    • 9p21 and Coronary Artery Calcification (rs10757278)CARDIA and ADVANCE studiesGroup OR pCaucasian 1.37 0.0018African Am 1.18 0.61Hispanic 1.61 0.20East Asian 1.58 0.17Majority 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 TestsConclusion:“Since family history is such a powerful predictor of CHD events, thecombination of simple and relatively inexpensive genetic tests to clarifyrisk, followed by noninvasive imaging in the high risk population, allowsidentification of a group most deserving of aggressive and individualizedtreatment.” (Current Athero Reports 2011;epub Aug 10)
    • Agenda1. Is there a Need for Genetic CVD Testing?2. Can Gene Tests Improve on what we already have?3. Genetics and noninvasive Imaging4. Families  2011 CGHDI
    • Premature CAD & 9p21“Entire families sometimes show this tendency to earlyarteriosclerosis. A tendency which cannot be explained in any otherway than that in the make-up of the machine bad material wasused 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 onCHD risk, the time has come to apply this knowledge in routineclinical practice in order to improve patient care. Indeed, inmay be past time. In 1989 Karl Berg wrote “Knowledge ofgenetic factors in the etiology of coronary heart disease has notso far been adequately utilized in attempts to combatpremature CHD. The time has now come to utilize geneticinformation in a setting of family-oriented preventivemedicine.
    • 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)
    • Conclusions1. CHD is in large part a Gene / Environment Disease2. 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.