1 / 63

Planned NIH Study: Comparing SHAPE with Status Quo

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 .

hana
Download Presentation

Planned NIH Study: Comparing SHAPE with Status Quo

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

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. “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 Grundy. Circulation 2008;117:569-573

  4. “Imaging has at least 3 virtues” 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;117:569-573 “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. Prognostic Power of CAC in Asymptomatic Patients Taylor (16) 1634 42 5.6 CAC>0 CAC 0 9.3 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%

  8. 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

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

  10. “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?” “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: 1085-7

  11. 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. Smith. BMJ 2003;327:1459–61

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

  13. “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;1118-1120

  14. CAC Absolute Event Rates in Asymptomatic Patients Annual Event Rate (%) St. Francis BeckerMESA HNRRotterdam N46131726 6722 41291795 f/u (yrs) 4.33.3 3.8 5 3.3 Age 62.2 57.7 60 71 CAC CACCACCAC 0 0.130-10 0.24 0.110.170-100 0.7 1-100 0.2311-100 1.32 0.59 0.28 100-400 1.284.6100-300 1.43 0.66100-400 1.64 >400 3.265.3>300 2.87 1.65 400-1000 2.25 >1000 3.7

  15. Summary of CAC Absolute Event Rates CAC FRS Risk 10 yr event rate 0 very low 1.1-1.7 % 1-100 low 2.3-5.9 % 100-400 intermediate 12.8-16.4 % >400 high 22.5-28.6 % >1000 very high 37 %

  16. Reclassification of FRS Risk by CAC Primary Prevention Outcome Studies Study % Reclassified N Age Follow up (yrs) MESA 5878 62.2 5.8 FRS 0-6% 11.6% FRS 6-20% 54.4% FRS>20% 35.8% NRI 25% Heinz Nixdorf 4487 45-75 5.0 FRS<10% 15.0% FRS 10-20% 65.6% FRS>20% 34.2% NRI 22.4% Rotterdam 2028 69.6 9.2 FRS<10% 12% FRS 10-20% 52% FRS>20% 34% NRI 19% Hecht. J Diabetes. 2012: In Press

  17. Distribution of CAC by FRS in MESA: Potential Implications for Coronary Risk Assessment 5660 asymptomatic pts CAC Prevalence >0 46.4% >100 20.6% >300 10.1% FRS CAC>300 NNS 0-2.5% 1.7% 59.7 2.6-5% 4.4% 22.7 5.1 -7.5% 7.5% 13.4 7.6-10% 13.1% 7.6 10.1-15% 15.6% 6.4 15.1-20% 24% 4.2 >20% 30% 3.3 Okwuosa. JACC 2011;57:1838–45

  18. Interplay of CAC and Traditional Risk Factors for Prediction of All-Cause Mortality in Asymptomatic Individuals 44, 052asymptomatic pts 5.6±2.6y f/u RF: current cigarette smoking dyslipidemia diabetes mellitus hypertension 0 CAC RF 0 1 2 >3 5 y all cause 99.7% 99.3% 99.3% 99.0% mortality Events/1000 person y 0 RF, CAC400 16.89 ≥3 RFs,CAC 0 2.72 Nasir. Circ Cardiovasc Imaging. 2012; 5:467-473

  19. Interplay of CAC and Traditional Risk Factors for Prediction of All-Cause Mortality in Asymptomatic Individuals Nasir. Circ Cardiovasc Imaging. 2012; 5:467-473

  20. Yield of Screening for CAC in Early Middle-Age Adults Based on the 10-Year FRS: The CARDIA Study 2831 asymptomatic pts 33-45y FRS >0 NNS >100 NNS Total 9.9% 1.8% 0-2.5% 7.3% 14 1.3% 79 2.6-5% 20.2% 5 2.4% 41 5.1-10% 19.1% 5 3.5% 29 >10% 44.8% 2 17.2% 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 Okwuosa . JACCImg 2012;5:923–30

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

  22. 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

  23. 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

  24. The Things to Come of SHAPE: Cost and Effectiveness of Cardiovascular Prevention 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 500,000 250,000 400,000 Expected deaths 100,000 50,000 80,000 Prevented events 150,000 75,000 120,000 LYEs 900,000 450,000 720,000 Prevented deaths 30,000 15,000 24,000 Life-years 390,000 195,000 312,000 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 500,000 250,000 400,000 Expected deaths 100,000 50,000 80,000 Prevented events 150,000 75,000 120,000 LYEs 900,000 450,000 720,000 Prevented deaths 30,000 15,000 24,000 Life-years 390,000 195,000 312,000 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 Cost/LYE $23,333 $18,444 $23,611 CAC $400 Diamond & Kaul. Am J Cardiol 2007;99:1013–5

  25. The Things to Come of SHAPE: Cost and Effectiveness of Cardiovascular Prevention 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 500,000 250,000 400,000 Expected deaths 100,000 50,000 80,000 Prevented events 150,000 75,000 120,000 LYEs 900,000 450,000 720,000 Prevented deaths 30,000 15,000 24,000 Life-years 390,000 195,000 312,000 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 500,000 250,000 400,000 Expected deaths 100,000 50,000 80,000 Prevented events 150,000 75,000 120,000 LYEs 900,000 450,000 720,000 Prevented deaths 30,000 15,000 24,000 Life-years 390,000 195,000 312,000 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 Cost/LYE $23,333 $18,444 $23,611 Cost/LYE $23,333 $18,444 $2,778 CAC $100 Diamond & Kaul. Am J Cardiol 2007;99:1013–5

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

  27. 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

  28. 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?

  29. 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

  30. 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

  31. 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

  32. Primary Assumptions for Sample Size

  33. Assumed Effect Sizes • 40 mg Atorvastatin for CAC>0 and ≤100 • 80 mg for CAC > 100 • Data sources • 0.78: RR for a 1 mmol/L LDL reduction (Cholesterol Treatment Trialists’ (CTT) Collaboration,Lancet, November 2010. DOI:10.1016/S0140-6736(10)61350-5.) • 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 2010. DOI:10.1016/S0140-6736(10)61350-5.) • 0.62: Reduction in LDL (mmol/L) for 80 vs. 10 mg (TNT. LaRosa JC, et al. NEJM 2005;352:1425-35.)

  34. 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

  35. Distribution of CAC Scores • Based on MESA participants without diabetes • Weighted using our expected racial distribution

  36. CHD Event Rates by CAC • Based on MESA participants without diabetes and with FRS 5 to <10% • Assumes exponential model for conversion

  37. Statin Dose Distributions • Adherence estimates untested group • Kuklina EV, et al. JAMA. 2009;302:2104-10 • Adherence estimates CAC-tested group • EISNER Study (unpublished data) • Kalia NK, et al. Atherosclerosis 2006; 185:394–9.

  38. Secondary Assumptions for Sample Size

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

  40. 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 Since ~50% will have 0 CAC, and will contribute very few events, it may be difficult to demonstrate a positive result 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

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

  42. 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,bIntrisk

  43. CIMT in Cardiovascular Risk Prediction: A Meta-analysis 14 population-based cohorts, 45 828 pts Median f/u 11 y, 4007 first MI or CVA C statistic NRI FRS 0.757 FRS+CIMT 0.759 0.008 (all pts) 0.036 (IR pts) CIMT (per 0.1mm increase) “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.” Den Ruijter. JAMA. 2012;308:796-803

  44. “High Risk Plaque Initiative”: Bio-Image Study • Methods: 6,100 asymptomatic intermediate risk pts • Carotid US IMT + plaque: All cases: Bilateral transverse sweep proximal to distal– ”manual 3D-like. Last 3,800 cases: Bilateral automated 3D recording • CAC: MDCT • Other tests: ABI, Abd US • 2.000 with “positive” findings: CCTA and/or carotid MRA • All 6,100 followed for 3 years; compared to a 1,300 non-imaging cohort. • End-points: Death, MI and stroke. Sillesen. SHAPE 2010

  45. Carotid Plaque Burden as a Measure of Subclinical Atherosclerosis: High Risk Plaque Bioimage Study 6101 asymptomatic pts; mean age 68.8y Int FRS (6-20%) 65.3% Carotid plaque 78% Abnl ABI 10% AAD >20mm 28% CAC 68% 0 32.1% 1-100 29.0% 101-400 22.2% >400 16.8% Association with CAC Marker N Multivariate Wald Chi p HR Square Plaque burden 5927 T3 4.79 450.0 <0.0001 T2 2.73 T1 1.70 CIMT (continous) 5923 1.14 24.0 <0.0001 CIMT (quartiles) 5923 Q4 1.46 28.5 <0.0001 Q3 1.21 Q2 1.13 Aortic diameter 4940 1.05 2.9 0.091 ABI 5879 1.65 35.2 <0.0001 Sillesen. J Am CollCardiolImg 2012;5:681–9

  46. Framingham and Plaque Presence

  47. Carotid Plaque Presence/Absence

More Related