Transcript IMPROVE IT - LBCT Final
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
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Risk Differences for 1000 Patients per Year with Ezetimibe/Simva
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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