Background: First vs Total Events

1. Reduction in Total (First and Recurrent) Cardiovascular Events with Ezetimibe/Simvastatin compared with Simvastatin Alone post ACS in the IMPROVE-IT Trial Sabina A. Murphy, Christopher Cannon, Robert Giugliano, Michael Blazing, Thomas Musliner, Andrew Tershakovec, Jennifer White, Kelly Im, Naveen Deenadayalu, Haral Darius, WitoldRuzyllo, Andrew Tonkin, Uma Kher, Robert Califf, Eugene Braunwald On behalf of the IMPROVE IT Investigators

2. Background: First vs Total Events • Analysis of long-term ACS trials often use survival analysis methods that take into account the first event a patient experiences during trial • Cox proportional hazards model • However, subjects with a non-fatal event continue to be followed during the trial and can experience additional events • All events, not just first, important to patients and clinicians

3. Background: Cholesterol Lowering • Lowering LDL cholesterol (LDL-C) has been a mainstay of primary and secondary CV prevention • Evidence from trials show reduction with high-intensity statins in total as well as first events post ACS • IMPROVE-IT trial evaluated whether ezetimibe added to simvastatin would provide a clinical benefit compared with simvastatin therapy alone Murphy SA, et al. JACC 2009;54:2358–62 Tikkanen, MJ et al. JACC 2009;54:2353–7

4. Study Design Patients stabilized post ACS ≤ 10 days: LDL-C 50–125*mg/dL (or 50–100**mg/dL if prior lipid-lowering Rx) Standard Medical & Interventional Therapy N=18,144 Simvastatin 40 mg Ezetimibe / Simvastatin 10 / 40 mg Duration: Minimum 2 ½-year follow-up (5314 events) Primary Endpoint: CV death, MI, hospital admission for UA, coronary revascularization (≥ 30 days after randomization), or stroke Cannon CP AHJ 2008;156:826-32; Califf RM NEJM 2009;361:712-7; Blazing MA AHJ 2014;168:205-12

5. Primary and 3 Prespecified Secondary Endpoints — First Events 0.936 0.948 0.912 0.945 0.8 1.0 1.1 *7-year event rates (%) Ezetimibe/Simva Better Simva Better UA, documented unstable angina requiring rehospitalization; Cor Revasc, coronary revascularization (≥30 days after randomization); All D, all-cause death; CHD, coronary heart disease death; All Revasc, coronary and non-coronary revascularization (≥30 days) Cannon CP et al, AHA 2014

6. Hypothesis • We hypothesized that combination ezetimibe/simvastatin would also reduce total events (first + recurrent), compared with simvastatin alone during the median 6-year follow-up after an acute coronary syndrome in IMPROVE-IT

7. Methods Negative Binomial Model - Primary • Modified Poisson model • Counts of total events • Included exposure time in model Wei, Lin and Weissfeld Model - Sensitivity • Extension of survival models based on the Cox proportional hazards • First 4 events included

8. Number of Primary Endpoint Events First Event Additional Events Revasc Total N=9545 Revasc

9. Total Primary Endpoint Events Total N=9545

10. Total Primary Endpoint Events 4983 4562 Total Events RR 0.91P=0.007 -421 -251 Additional Events RR 0.88 (0.79-0.98) # Events 1st Event HR 0.936P=0.016 -170 Simvastatin Alone Ezetimibe Simvastatin

11. Secondary EP: CHD death, MI, urgent revascularization Events 2670 Total Events RR 0.85 P=0.002 2303 -367 Additional Events RR 0.79 (0.69-0.91) -241 # Events 1st Event HR 0.912P=0.016 -126 Simvastatin Alone Ezetimibe Simvastatin

12. Primary and 3 Prespecified Secondary Endpoints — Total Events 0.91 0.92 0.85 0.93 0.88 0.7 1.2 1.0 Ezetimibe/Simva Better Simva Better

13. Total PEP Events by Type of Event 4983 4562 Total NF MI RR 0.87 p=0.004 Total NF Stroke RR 0.77 p=0.005 # Events Simvastatin Alone Ezetimibe Simvastatin

14. Sensitivity Analysis: Wei, Lin, WeissfeldModel for Primary Endpoint Model HR 0.93, 95% CI 0.89, 0.99, p=0.01 0.6 1.3 1.0 Ezetimibe/Simva Better Simva Better

15. Total Primary Endpoint Events Risk Differences for 1000 Patients per Year with Ezetimibe/Simva * * * 0 0 Events/1000 Patients/Year -4 -5 -11 * p<0.05; others NS

16. Conclusions • Lipid lowering therapy with ezetimibe/simvastatinimproved clinical efficacy with reductions in totalprimary endpoint events compared with simvastatin alone, driven by reductions in MI, stroke, and urgent revasc • Taking into account total events more than doubled the number of events prevented with ezetimibe/simvastatin combination

17. Conclusions • These data provide further support of the benefit of continuation of intensive combination lipid lowering therapy after a recurrent CV event • Analyses of recurrent events are important as total events have implications: • Patient morbidity • Need for recurrent hospitalizations • Costs • These considerations not always accounted for when analyzing first events only