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Reduction in Total (First and Recurrent) Cardiovascular Events with Ezetimibe/Simvastatin compared with Simvastatin Alone post ACS in the IMPROVE-IT Trial.

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Presentation on theme: "Reduction in Total (First and Recurrent) Cardiovascular Events with Ezetimibe/Simvastatin compared with Simvastatin Alone post ACS in the IMPROVE-IT Trial."— Presentation transcript:

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, Witold Ruzyllo, 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 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 Ezetimibe / Simvastatin 10 / 40 mg Simvastatin 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 N=18,144 Study Design Cannon CP AHJ 2008;156:826-32; Califf RM NEJM 2009;361:712-7; Blazing MA AHJ 2014;168:205-12

5 Simva*EZ/Simva*p-value Primary CVD/MI/UA/Cor Revasc/CVA Secondary # All D/MI/UA/Cor Revasc/CVA Secondary # CHD/MI/Urgent Cor Revasc Secondary # CVD/MI/UA/All Revasc/CVA 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) *7-year event rates (%) Primary and 3 Prespecified Secondary Endpoints — First Events 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 Revasc Total N=9545 First Event Additional Events

9 Total Primary Endpoint Events Total N=9545

10 Total Primary Endpoint Events # Events # Events Ezetimibe Simvastatin Simvastatin Alone Total Events RR 0.91 P=0.007 Additional Events RR 0.88 ( ) 1st Event HR P=

11 Secondary EP: CHD death, MI, urgent revascularization Events # Events # Events Ezetimibe Simvastatin Simvastatin Alone Total Events RR 0.85 P=0.002 Additional Events RR 0.79 ( ) 1st Event HR P=

12 Primary and 3 Prespecified Secondary Endpoints — Total Events Ezetimibe/Simva Better Simva Better p-value Primary CVD/MI/UA/Cor Revasc/CVA Secondary #1 All D/MI/UA/Cor Revasc/CVA Secondary #2 CHD/MI/Urgent Cor Revasc Secondary #3 CVD/MI/UA/All Revasc/CVA 0.02 Exploratory CVD/MI/CVA

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

14 First Event (n=5,314) Second Event (n=2,297) Third Event (n=972) Fourth Event (n=456) Model Average HR Sensitivity Analysis: Wei, Lin, Weissfeld Model for Primary Endpoint Ezetimibe/Simva Better Simva Better Model HR 0.93, 95% CI 0.89, 0.99, p=0.01

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

16 Conclusions ➢ Lipid lowering therapy with ezetimibe/simvastatin improved clinical efficacy with reductions in total primary 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


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