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Planned NIH Study: Comparing SHAPE with Status Quo Harvey S. Hecht, MD, FACC, FSCCT Associate Director of Cardiovascular Imaging Professor of Medicine,

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Presentation on theme: "Planned NIH Study: Comparing SHAPE with Status Quo Harvey S. Hecht, MD, FACC, FSCCT Associate Director of Cardiovascular Imaging Professor of Medicine,"— Presentation transcript:

1 Planned NIH Study: Comparing SHAPE with Status Quo Harvey S. Hecht, MD, FACC, FSCCT Associate Director of Cardiovascular Imaging Professor of Medicine, Mount Sinai School of Medicine

2 Do we need an NIH RCT?

3 Grundy. Circulation 2008;117: “Imaging has at least 3 virtues” It individualizes risk assessment beyond use of age, which is a less reliable surrogate for atherosclerosis burden It provides an integrated assessment of the lifetime exposure to risk factors It identifies individuals who are susceptible to developing atherosclerosis beyond established risk factors

4 Thus, for primary prevention, a recommendation could be established that detection of significant plaque burden is a preferred strategy for initiation of LDL-lowering drugs. With such a recommendation, major risk factors and emerging risk factors could be used as a guide for selecting subjects for imaging more than as a primary guide for therapy Once subclinical atherosclerosis is detected, intensity of drug therapy could be adjusted for plaque burden Grundy. Circulation 2008;117: “Imaging has at least 3 virtues” “The most important role of risk factors may be to identify the modifiable targets of risk reduction in patients with risk already established by clinical events or significant CAC.” Hecht. Risk factors revisited. AJC 2003;93:73-5

5 N Mean Age (years) Follow up (years) Calcium Score Cutoff Comparator Group for RR Calculat Relative Risk Ratio Arad (1) 1, CAC>160 CAC< Park (2) CAC >142.1 CAC < Raggi (3) Top Quartile Lowest Quartile 13 Wong (4) Top Quartile (>270) First Quartile8.8 Kondos (5)5, CACNo CAC10.5 Greenland (6)1, CAC>300No CAC3.9 Shaw (7) 10, CAC >400CAC <108.4 Arad (8)5, CAC ≥ 100CAC < Taylor (9) CAC >44CAC=011.8 Vliegenthart (10) CAC>1000CAC< CAC CAC< Budoff (11)25, CAC>400CAC 09.2 Lagoski (12) CAC>0CAC 06.5 Becker (13) CAC>400CAC men 7.9 women Detrano (14) CAC>300CAC Erbel (15) >75 th %<25 th %11.1 men 3.2 women Taylor (16) CAC>0 CAC Prognostic Power of CAC in Asymptomatic Patients In every study, CAC has been superior to and significantly added to the area under the ROC curve for all risk factor based aalyses!

6 Naghavi, Falk, Hecht., et al. AJC 2006

7 5%

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9 Comparison of ACC/AHA 2010 and SHAPE ACC/AHA SHAPE Coronary Calcium High (>20%) NA I Intermediate (10-20%) IIa I Low to intermediate (6-10%) IIb I Lower (<6%) III +FH, DM Treatment guidelines no yes Downgrade risk yes yes Upgrade risk yes yes

10 Never Underestimate the Power of People Who Cling to Each Other to Perpetuate the Status Quo We demand outcome studies! Stubborn Resistance

11 “It is incumbent on the cardiology community to temper the inflexible need for randomized trials with the reality of 565,000 patients presenting with a myocardial infarction annually as their first symptom, 95% of whom could be identified as high risk by CAC and aggressively treated to significantly reduce events.” AJC 2008;101: “If neither the CAC score nor the Framingham Risk Score has outcome data to support it, why not use the one with the greater prognostic power?”

12 Smith. BMJ 2003;327:1459–61 Conclusions: As with many interventions intended to prevent ill health, the effectiveness of parachutes has not been subjected to rigorous evaluation by using randomised controlled trials. Advocates of evidence based medicine have criticised the adoption of interventions evaluated by using only observational data. We think that everyone might benefit if the most radical protagonists of evidence based medicine organised and participated in a double blind, randomised, placebo controlled, crossover trial of the parachute.

13 Is this a joke? High Risk Treatment Jumping from an airplane Parachute High CAC Aggressive medical rx

14 “Randomized controlled trials are not necessary to prove that treatment of high-risk patients saves lives. If a randomized controlled trial were performed and failed to show that treatment of CAC-identified high-risk patients saved more lives, the fault would lie with the treatment rather than the test.” Hecht. JACC 2010;55;

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17 Annual Event Rate (%) St. Francis Becker MESA HNR Rotterdam N f/u (yrs) Age CAC CAC > > > CAC Absolute Event Rates in Asymptomatic Patients

18 CAC FRS Risk 10 yr event rate 0 very low % low % intermediate % >400 high % >1000 very high 37 % Summary of CAC Absolute Event Rates

19 Study % Reclassified N Age Follow up (yrs) MESA FRS 0-6% 11.6% FRS 6-20% 54.4% FRS>20% 35.8% NRI 25% Heinz Nixdorf FRS<10% 15.0% FRS 10-20% 65.6% FRS>20% 34.2% NRI 22.4% Rotterdam FRS<10% 12% FRS 10-20% 52% FRS>20% 34% NRI 19% Reclassification of FRS Risk by CAC Primary Prevention Outcome Studies Hecht. J Diabetes. 2012: In Press

20 Distribution of CAC by FRS in MESA: Potential Implications for Coronary Risk Assessment Okwuosa. JACC 2011;57:1838–45 FRS CAC>300 NNS 0-2.5% 1.7% % 4.4% % 7.5% % 13.1% % 15.6% % 24% 4.2 >20% 30% 3.3 CAC Prevalence >0 46.4% > % > % 5660 asymptomatic pts

21 Interplay of CAC and Traditional Risk Factors for Prediction of All-Cause Mortality in Asymptomatic Individuals Nasir. Circ Cardiovasc Imaging. 2012; 5: , 052 asymptomatic pts 5.6±2.6y f/u RF: current cigarette smoking dyslipidemia diabetes mellitus hypertension Events/1000 person y 0 RF, CAC ≥3 RFs, CAC CAC RF >3 5 y all cause 99.7% 99.3% 99.3% 99.0% mortality

22 Interplay of CAC and Traditional Risk Factors for Prediction of All-Cause Mortality in Asymptomatic Individuals Nasir. Circ Cardiovasc Imaging. 2012; 5:

23 Yield of Screening for CAC in Early Middle-Age Adults Based on the 10-Year FRS: The CARDIA Study Okwuosa. JACCImg 2012;5:923– asymptomatic pts 33-45y FRS >0 NNS >100 NNS Total 9.9% 1.8% 0-2.5% 7.3% % % 20.2% 5 2.4% % 19.1% 5 3.5% 29 >10% 44.8% % 6 >5% 22.7 % 3.6 >2.5% 23.0% 4.3 >10% FRS cutoff Editorial suggests >5% FRS cutoff: high risk with >0 CAC in >5% FRS in PACCS study

24 The Value of Imaging in Enhancing the Wellness of Your Heart Trial: The VIEW Your Heart Trial February 16, 2011

25 Background CAC known to predict CHD events, beyond FRS CAC testing increasing in population Value of CAC testing to enhance CHD prevention unknown Costs of CAC testing potentially great Risks of CAC testing small but real Trial of value of CAC testing to inform CHD prevention needed

26 Background CAC known to predict CHD events, beyond FRS CAC testing increasing in population Value of CAC testing to enhance CHD prevention unknown Costs of CAC testing potentially great Risks of CAC testing small but real Trial of value of CAC testing to inform CHD prevention needed

27 Performance of alternative strategies for cardiovascular prevention____ Metric Treat All NCEP SHAPE___ Test targets 0 50 million 50 million Treatment candidates 50 million 15 million 12.5 million Expected events 500, , ,000 Expected deaths 100,000 50,000 80,000 Prevented events 150,000 75, ,000 LYEs 900, , ,000 Prevented deaths 30,000 15,000 24,000 Life-years 390, , ,000 Testing cost 0 $5 billion $20 billion Treatment cost $36 billion $10.8 billion $9 billion Gross cost $36 billion $15.8 billion $29 billion Treatment savings $15 billion $7.5 billion $12 billion Net cost $21 billion $8.3 billion $17 billion Cost/LYE $23,333 $18,444 $23,611 Performance of alternative strategies for cardiovascular prevention____ Metric Treat All NCEP SHAPE___ Test targets 0 50 million 50 million Treatment candidates 50 million 15 million 12.5 million Expected events 500, , ,000 Expected deaths 100,000 50,000 80,000 Prevented events 150,000 75, ,000 LYEs 900, , ,000 Prevented deaths 30,000 15,000 24,000 Life-years 390, , ,000 Testing cost 0 $5 billion $20 billion Treatment cost $36 billion $10.8 billion $9 billion Gross cost $36 billion $15.8 billion $29 billion Treatment savings $15 billion $7.5 billion $12 billion Net cost $21 billion $8.3 billion $17 billion Cost/LYE $23,333 $18,444 $2,778 Diamond & Kaul. Am J Cardiol 2007;99:1013–5 The Things to Come of SHAPE: Cost and Effectiveness of Cardiovascular Prevention Cost/LYE $23,333 $18,444 $23,611 CAC $400

28 Performance of alternative strategies for cardiovascular prevention____ Metric Treat All NCEP SHAPE___ Test targets 0 50 million 50 million Treatment candidates 50 million 15 million 12.5 million Expected events 500, , ,000 Expected deaths 100,000 50,000 80,000 Prevented events 150,000 75, ,000 LYEs 900, , ,000 Prevented deaths 30,000 15,000 24,000 Life-years 390, , ,000 Testing cost 0 $5 billion $20 billion Treatment cost $36 billion $10.8 billion $9 billion Gross cost $36 billion $15.8 billion $29 billion Treatment savings $15 billion $7.5 billion $12 billion Net cost $21 billion $8.3 billion $17 billion Cost/LYE $23,333 $18,444 $23,611 Performance of alternative strategies for cardiovascular prevention____ Metric Treat All NCEP SHAPE___ Test targets 0 50 million 50 million Treatment candidates 50 million 15 million 12.5 million Expected events 500, , ,000 Expected deaths 100,000 50,000 80,000 Prevented events 150,000 75, ,000 LYEs 900, , ,000 Prevented deaths 30,000 15,000 24,000 Life-years 390, , ,000 Testing cost 0 $5 billion $5 billion Treatment cost $36 billion $10.8 billion $9 billion Gross cost $36 billion $15.8 billion $14 billion Treatment savings $15 billion $7.5 billion $12 billion Net cost $21 billion $8.3 billion $2 billion Cost/LYE $23,333 $18,444 $2,778 Diamond & Kaul. Am J Cardiol 2007;99:1013–5 The Things to Come of SHAPE: Cost and Effectiveness of Cardiovascular Prevention CAC $100 Cost/LYE $23,333 $18,444 $23,611Cost/LYE $23,333 $18,444 $2,778

29 Diamond & Kaul. Am J Cardiol 2007;99:1013–5 The Things to Come of SHAPE: Cost and Effectiveness of Cardiovascular Prevention Net cost per LYE saved $32 $28 $22Net cost per LYE saved - $23 $28 $106 CAC $400 CAC $100

30 The AAPM Position Statement on Radiation Risks from Medical Imaging Procedures Policy date 12/13/2011 The American Association of Physicists in Medicine (AAPM) acknowledges that medical imaging procedures should be appropriate and conducted at the lowest radiation dose consistent with acquisition of the desired information. Discussion of risks related to radiation dose from medical imaging procedures should be accompanied by acknowledgement of the benefits of the procedures. Risks of medical imaging at effective doses below 50 mSv for single procedures or 100 mSv for multiple procedures over short time periods are too low to be detectable and may be nonexistent. Predictions of hypothetical cancer incidence and deaths in patient populations exposed to such low doses are highly speculative and should be discouraged. These predictions are harmful because they lead to sensationalistic articles in the public media that cause some patients and parents to refuse medical imaging procedures, placing them at substantial risk by not receiving the clinical benefits of the prescribed procedures. AAPM members continually strive to improve medical imaging by lowering radiation levels and maximizing benefits of imaging procedures involving ionizing radiation

31 Study Question Is a coronary heart disease (CHD) risk management strategy that is guided by the coronary artery calcium (CAC) score associated with fewer CHD events than usual care among individuals who are at relatively low risk? Specifically: In a population with 10-year FRS for CHD of 5 to <10%, does treatment of CAC+ persons with statin therapy lead to fewer CHD events versus usual care?

32 Study Population Screening criteria –Age ≥ 45 for men, ≥55 for women –Free of DM, CVD –Not treated with statins or other lipid-lowering medication –Lipids, BP, smoking measured within 1 year –Target people 5 to <10% 10-year Framingham risk for CHD Inclusion criteria –Asymptomatic men and women with Framingham risk score 5 – 9.9% + LDL < 160 (may add FRS 10–19.9% + LDL < 130 or <100) –Age ≥ 45 for men, ≥55 for women –No statin use within the previous 6 weeks –No evidence of prior CVD, diabetes, or other CHD risk-equivalent (e.g., PAD) Exclusion criteria –Known CVD –Contraindication to statin therapy

33 Intervention For CAC = 0, no medication recommended For CAC > 0, statin recommended (dose depends on score) –40 mg Atorvastatin for CAC > 0 and ≤ 100 –80 mg Atorvastatin for CAC > 100 Medication provided by study

34 Outcomes Primary: Major CHD event –Composite of CHD deaths and nonfatal acute coronary syndromes (includes revascularization) –Like MESA’s all CHD outcome Secondary –Components of primary outcome –Revascularization and resuscitated cardiac arrest –HRQL/Cost effectiveness –Adherence –Incidental findings

35 Primary Assumptions for Sample Size AssumptionSource Framingham risk score (FRS) distribution at baseline Recruitment targets with some noise Conditional distribution of CAC score by FRS MESA Event rates by CAC scoreMESA Statin dose distributions by FRS and CAC Literature (observational data) Effect sizes (hazard ratios) for statin treatment Literature (trial data) Racial BreakdownAssumed to be 75% white, 2% Chinese, 15% African American, and 8% Hispanic (using the MESA categories)

36 Assumed Effect Sizes 40 mg Atorvastatin for CAC>0 and ≤ mg for CAC > 100 Data sources –0.78: RR for a 1 mmol/L LDL reduction (Cholesterol Treatment Trialists’ (CTT) Collaboration, Lancet, November DOI: /S (10) ) –1.3: Reduction in LDL (mmol/L) for 10 mg Atorvastatin vs. placebo (ASCOT-LLA. Sever PS, et al. Lancet 2003; 361: 1149–58.) –0.41: effect of atorvastatin 40 vs. 10, given estimate of 0.62 mmol/L reduction for 80 vs. 10 (Cholesterol Treatment Trialists’ (CTT) Collaboration, Lancet, November DOI: /S (10) ) –0.62: Reduction in LDL (mmol/L) for 80 vs. 10 mg (TNT. LaRosa JC, et al. NEJM 2005;352: ) DoseHR 0 mg1 40 mg ≈ mg ≈0.621

37 Framingham Risk Score Distribution Target people 5 to <10% 10-year Framingham risk for CHD (Wilson et al, Circulation 1998) Final FRS score determined at baseline, expect some in other categories due to variability FRSProportion <5%7.5 % 5 to <10%84.5 % 10 to <20%7.5 % ≥20%0.5 %

38 Distribution of CAC Scores Based on MESA participants without diabetes Weighted using our expected racial distribution CAC Score FRS for CHD0>0 to ≤100>100 <5%53.5%25.3%21.2% 5 to <10%48.7%30.2%21.0% 10 to <20%32.2%29.7%38.1% ≥20%32.2%29.7%38.1% Total47.7%29.8%22.5%

39 CHD Event Rates by CAC Based on MESA participants without diabetes and with FRS 5 to <10% Assumes exponential model for conversion CAC ScoreOne Year Rate (%) Ten Year Rate (%) Hazard Ratio >0 to ≤ >

40 Statin Dose Distributions Adherence estimates untested group –Kuklina EV, et al. JAMA. 2009;302: Adherence estimates CAC-tested group –EISNER Study (unpublished data) –Kalia NK, et al. Atherosclerosis 2006; 185:394–9. UntestedTested FRS0 mg10 mg80 mgCAC0 mg10 mg80 mg <5% to <10% >0 to ≤ to <20% > ≥20%

41 Secondary Assumptions for Sample Size AssumptionValue Significance Level0.05 (two-sided) Dropout2 %/year Recruitment2 years (uniform) Study Length6 years (5 year average follow-up) Proportion tested0.5

42 Sample Size 20,968 for 80% power 28,068 for 90% power Budget $70 million

43 Comparison of ACC/AHA 2010, SHAPE and NIH ACC/AHA SHAPE NIH Coronary Calcium High (>20%) na I no Intermediate (10-20%) IIa I no Low to intermediate (6-10%) IIb I TBD Lower (<6%) III +FH, DM no Treatment guidelines no yes TBD Downgrade risk yes yes TBD Upgrade risk yes yes TBD After 8 years and $70 million a positive result will reinforce CAC use only in low to intermediate group (6-10%) unless intermediate group is added Since ~50% will have 0 CAC, and will contribute very few events, it may be difficult to demonstrate a positive result

44 Randomized Controlled Trials, the guide(line) dog But there are no outcome studies for high, intermediate and low risk patients!

45 Comparison of ACC/AHA 2010 and SHAPE ACC/AHA SHAPE Coronary Calcium High (>20%) NA I Intermediate (10-20%) IIa I Low to intermediate (6-10%) IIb I Lower (<6%) III +FH, DM Treatment guidelines no yes Downgrade risk yes yes Upgrade risk yes yes Carotid IMT/Plaque High NA I Intermediate (10-20%) IIa I Low to intermediate (6-10%) NA I Lower (<6%) NA +FH, DM CRP IIa,b Int risk

46 CIMT in Cardiovascular Risk Prediction: A Meta-analysis 14 population-based cohorts, pts Median f/u 11 y, 4007 first MI or CVA CIMT (per 0.1mm increase) C statistic NRI FRS FRS+CIMT (all pts) (IR pts) Den Ruijter. JAMA. 2012;308: “The addition of CIMT to the FRS was associated with small improvement in 10-year risk prediction of first-time MI or CVA, but this improvement is unlikely to be of clinical importance.”

47 “High Risk Plaque Initiative”: Bio-Image Study Methods: 6,100 asymptomatic intermediate risk pts Methods: 6,100 asymptomatic intermediate risk pts Carotid US IMT + plaque: Carotid US IMT + plaque: All cases: Bilateral transverse sweep proximal to distal– ”manual 3D-like. Last 3,800 cases: Bilateral automated 3D recording All cases: Bilateral transverse sweep proximal to distal– ”manual 3D-like. Last 3,800 cases: Bilateral automated 3D recording CAC: MDCT CAC: MDCT Other tests: ABI, Abd US Other tests: ABI, Abd US with “positive” findings: CCTA and/or carotid MRA with “positive” findings: CCTA and/or carotid MRA All 6,100 followed for 3 years; compared to a 1,300 non-imaging cohort. All 6,100 followed for 3 years; compared to a 1,300 non-imaging cohort. End-points: Death, MI and stroke. End-points: Death, MI and stroke. Methods: 6,100 asymptomatic intermediate risk pts Methods: 6,100 asymptomatic intermediate risk pts Carotid US IMT + plaque: Carotid US IMT + plaque: All cases: Bilateral transverse sweep proximal to distal– ”manual 3D-like. Last 3,800 cases: Bilateral automated 3D recording All cases: Bilateral transverse sweep proximal to distal– ”manual 3D-like. Last 3,800 cases: Bilateral automated 3D recording CAC: MDCT CAC: MDCT Other tests: ABI, Abd US Other tests: ABI, Abd US with “positive” findings: CCTA and/or carotid MRA with “positive” findings: CCTA and/or carotid MRA All 6,100 followed for 3 years; compared to a 1,300 non-imaging cohort. All 6,100 followed for 3 years; compared to a 1,300 non-imaging cohort. End-points: Death, MI and stroke. End-points: Death, MI and stroke. Sillesen. SHAPE 2010

48 Carotid Plaque Burden as a Measure of Subclinical Atherosclerosis: High Risk Plaque Bioimage Study Sillesen. J Am Coll Cardiol Img 2012;5:681–9 Marker N Multivariate Wald Chi p HR Square Plaque burden 5927 T < T T CIMT (continous) < CIMT (quartiles) 5923 Q < Q Q Aortic diameter ABI < Int FRS (6-20%) 65.3% Carotid plaque 78% Abnl ABI 10% AAD >20mm 28% 6101 asymptomatic pts; mean age 68.8y Association with CAC CAC 68% % % % > %

49 Framingham and Plaque Presence

50 Carotid Plaque Presence/Absence

51 Plaque presence and CAC

52 (n = 1456) (n = 1456) (n = 1457) (n = 1454) PHASE 1 - COMPARATIVE PREVALENCE BETWEEN DEGREE OF CAC AND DEGREE OF CAROTID PLAQUE BURDEN BY 3D SWEEP IMT vs CAC: NS U Baber, R Mehran, P Muntendam, M Garcia, H Sillesen, E Falk, V Fuster, 2012

53 PHASE 2 - BioImage And CardioScore: Significant Risk Prediction For Primary Events CACS 3D carotid ultrasound CardioSCORE blood test N=3557 for all plots that have 3D carotid US Cumulative Event Rate by Category P Muntendam, E Falk, V Fuster 2012

54 PHASE 2 - Significant Addition of Risk Prediction By CACS + Carotid US – Addition to FRS ? # # Based on Phase 1, Suspect a Very Significant Addition.

55 PHASE 1 - PLAQUE BURDEN - 3D US SWEEP PRIMARY EVENTS - N=186, 18 MONTHS Variables OR (95% CI) P value Chi-square Burden, > 4.20 cm ( ) < Burden, cm ( ) Burden, cm ( ) H Sillesen, E Falk, P Muntendam, V Fuster, JACC Img 2012 (Subm)

56 3D plaque analysis reveals that plaque is much more prevalent than previously thought 3D plaque analysis reveals that plaque is much more prevalent than previously thought Plaque tracks CAC; IMT does not Plaque tracks CAC; IMT does not High percentage (70%) of plaque in 0 CAC pts mandates plaque be evaluated with a minimum abnormal volume and a graded scale for risk assessment High percentage (70%) of plaque in 0 CAC pts mandates plaque be evaluated with a minimum abnormal volume and a graded scale for risk assessment HRP outcomes will affect screening recommendations HRP outcomes will affect screening recommendations 3D plaque analysis reveals that plaque is much more prevalent than previously thought 3D plaque analysis reveals that plaque is much more prevalent than previously thought Plaque tracks CAC; IMT does not Plaque tracks CAC; IMT does not High percentage (70%) of plaque in 0 CAC pts mandates plaque be evaluated with a minimum abnormal volume and a graded scale for risk assessment High percentage (70%) of plaque in 0 CAC pts mandates plaque be evaluated with a minimum abnormal volume and a graded scale for risk assessment HRP outcomes will affect screening recommendations HRP outcomes will affect screening recommendations “High Risk Plaque Initiative”: Bio-Image Study

57 Coronary Artery Calcium Score (CACS) or Carotid Plaque Burden 0 Carotid Plaque Carotid Plaque present Lowest Tertile Carotid Plaque Highest Tertile Carotid Plaque Middle Tertile Carotid Plaque CACS &<75 th % CACS>400 or >75 th % Lowest Risk Low Risk High Risk The 2 nd S.H.A.P.E. Guideline Intermediate Risk

58 Venkman: I make it a rule never to get involved with possessed people. Actually, it's more of a guideline than a rule... Guidelines vs. Rules Blumenthal JACC 2011;57:1601–3 We must avoid the “cognitive dissonance” that often impedes forward progress and confines guidelines to the necessity of the RCT, to optimize the care of our patients in light of the available evidence.

59 For patients undergoing risk evaluation: Superior doctors use CAC Mediocre doctors use the FRS and hope their patient is still alive when the RCT is complete Inferior doctors are so biased that they will never use CAC --Huang Dee: Nai-Ching (2600 BC First Chinese Medical Text)

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