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

Background: First vs Total Events

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Analysis of long-term ACS trials often use survival analysis methods that take into account the first event a patient experiences during trial

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Cox proportional hazards model

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However, subjects with a non-fatal event continue to be followed during the trial and can experience additional events

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All events, not just first, important to patients and clinicians

Background: Cholesterol Lowering

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Lowering LDL cholesterol (LDL-C) has been a mainstay of primary and secondary CV prevention

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Evidence from trials show reduction with high- intensity statins in total as well as first events post ACS

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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

Study Design

Patients stabilized post ACS ≤ 10 days:

LDL-C 50 –125*mg/dL (or 50–100**mg/dL if prior lipid-lowering Rx)

N=18,144

Standard Medical & Interventional Therapy

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

Primary and 3 Prespecified Secondary Endpoints — First Events

Primary CVD/MI/UA/Cor Revasc/CVA 0.936

Simva* EZ/Simva* p-value

34.7

32.7

0.016

0.948

Secondary #1 All D/MI/UA/Cor Revasc/CVA 40.3

38.7

0.034

Secondary #2 CHD/MI/Urgent Cor Revasc 0.912

18.9

17.5

0.016

0.945

Secondary #3 CVD/MI/UA/All Revasc/CVA 36.2

34.5

0.035

0.8

Ezetimibe/Simva Better 1.0

Simva Better 1.1

*7-year event rates (%) 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

Hypothesis

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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

Methods

Negative Binomial Model - Primary

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Modified Poisson model

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Counts of total events

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Included exposure time in model Wei, Lin and Weissfeld Model - Sensitivity

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Extension of survival models based on the Cox proportional hazards

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First 4 events included

Number of Primary Endpoint Events

First Event Additional Events Revasc Total N=9545 Revasc

Total Primary Endpoint Events

Total N=9545

Total Primary Endpoint Events

4983 Total Events RR 0.91

P=0.007

4562

Additional Events RR 0.88 (0.79-0.98) 1st Event HR 0.936

P=0.016

Simvastatin Alone Ezetimibe Simvastatin -421 -251 -170

Secondary EP: CHD death, MI, urgent revascularization Events

2670 Simvastatin Alone Total Events RR 0.85 P=0.002

Additional Events RR 0.79 (0.69-0.91) 1st Event HR 0.912

P=0.016

2303 -367 -241 -126 Ezetimibe Simvastatin

Primary and 3 Prespecified Secondary Endpoints — Total Events

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 Exploratory CVD/MI/CVA 0.7

0.85

0.88

0.91

0.92

Ezetimibe/Simva Better

p-value

0.007

0.93

1.0

0.009

0.002 0.02

0.002 Simva Better 1.2

Total PEP Events by Type of Event

4983 Total NF MI RR 0.87

p=0.004

4562 Total NF Stroke RR 0.77

p=0.005

Simvastatin Alone Ezetimibe Simvastatin

Sensitivity Analysis: Wei, Lin, Weissfeld Model for Primary Endpoint

Model HR 0.93, 95% CI 0.89, 0.99, p=0.01

First Event (n=5,314) Second Event (n=2,297) Third Event (n=972) Fourth Event (n=456) Model Average HR

0.6

Ezetimibe/Simva Better 1.0

Simva Better 1.3

Total Primary Endpoint Events

*

Risk Differences for 1000 Patients per Year with Ezetimibe/Simva

* *

0 0 -4 -5 -11

* p<0.05; others NS

Conclusions

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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

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Taking into account total events more than doubled the number of events prevented with ezetimibe/simvastatin combination

Conclusions

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These data provide further support of the benefit of continuation of intensive combination lipid lowering therapy after a recurrent CV event

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Analyses of recurrent events are important as total events have implications:

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Patient morbidity

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Need for recurrent hospitalizations

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Costs

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These considerations not always accounted for when analyzing first events only