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
➢ 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
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
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
Simva* EZ/Simva* p-value
0.936
Primary
CVD/MI/UA/Cor Revasc/CVA
0.948
Secondary #1
All D/MI/UA/Cor Revasc/CVA
0.912
Secondary #2
CHD/MI/Urgent Cor Revasc
0.945
Secondary #3
CVD/MI/UA/All Revasc/CVA
0.8
1.0
Ezetimibe/Simva
Better
1.1
Simva
Better
34.7
32.7
0.016
40.3
38.7
0.034
18.9
17.5
0.016
36.2
34.5
0.035
*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
➢ 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
➢ 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
Number of Primary Endpoint
Events
First
Event
Revasc
Additional
Events
Total
N=9545
Revasc
Total Primary Endpoint Events
Total
N=9545
Total Primary Endpoint Events
4983
# Events
Total Events
RR 0.91
P=0.007
Simvastatin
Alone
4562
-421
Additional
Events
RR 0.88
(0.79-0.98)
-251
1st Event
HR 0.936
P=0.016
-170
Ezetimibe
Simvastatin
Secondary EP: CHD death, MI,
urgent revascularization Events
2670
Total Events
RR 0.85
P=0.002
2303
# Events
Additional
Events
RR 0.79
(0.69-0.91)
-241
1st Event
HR 0.912
P=0.016
Simvastatin
Alone
-367
-126
Ezetimibe
Simvastatin
Primary and 3 Prespecified
Secondary Endpoints — Total Events
p-value
0.91
Primary
CVD/MI/UA/Cor Revasc/CVA
0.007
0.92
Secondary #1
All D/MI/UA/Cor Revasc/CVA
0.009
0.85
Secondary #2
CHD/MI/Urgent Cor Revasc
0.002
Secondary #3
CVD/MI/UA/All Revasc/CVA
0.93
0.02
Exploratory
CVD/MI/CVA
0.88
0.7
Ezetimibe/Simva
Better
0.002
1.0
Simva
Better
1.2
Total PEP Events by Type of
Event
4983
4562
# Events
Total NF MI
RR 0.87
p=0.004
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
Events/1000 Patients/Year
Risk Differences for 1000 Patients per Year
with Ezetimibe/Simva
*
*
*
0
-5
0
-4
-11
* p<0.05; others NS
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
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