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IMProved Reduction of
Outcomes: Vytorin Efficacy
International Trial
A Multicenter, Double-Blind, Randomized Study to
Establish the Clinical Benefit and Safety of Vytorin
(Ezetimibe/Simvastatin Tablet) vs Simvastatin
Monotherapy in High-Risk Subjects Presenting
With Acute Coronary Syndrome
Trial Leadership
Study Chairmen: Eugene Braunwald and Robert Califf
TIMI Study Group: Christopher Cannon Robert Giugliano
Amy McCagg Christina Pelland
Sabina Murphy Erin Bohula May
DCRI: Michael Blazing Craig Reist
Jennifer White Yuliya Lokhnygina
Curtis Campbell Cathy Martz
Merck: Thomas Musliner Andrew Tershakovec
Ann Kilian Rona Harmelin-Kadouri
Paul DeLucca Steve Bird
DSMB Chair: Scott Grundy
CEC Chair: Stephen Wiviott
National Lead Investigators and Steering
Committee (1158 sites, 39 Countries)
Enrique Gurfinkel¹
Argentina (331)
Philip Aylward
Andrew Tonkin*
Australia (116)
Gerald Maurer
Austria (249)
Frans Van de Werf
Belgium (249)
Jose C. Nicolau
Brazil (423)
Pierre Theroux
Paul Armstrong*
Jacques Genest*
Canada (1106)
Ramon Cobalan
Chile (152)
Daniel Isaza
Colombia (568)
Jindrich Spinar
Czech Rep (371)
Peer Grande²
Denmark (576)
Juri Voitk
Estonia (10)
Antero Kesaniemi
Finland (341)
Jean-Pierre Bassand
Michel Farnier*
France (268)
Harald Darius
Germany (935)
Matayas Keltai
Hungary (116)
Atul Mathur
Sanjay Mittal
Krishna Reddy
India (259)
Basil Lewis
Israel (589)
Gaetano DeFerrari
Italy (593)
Ton Oude Ophuis
J. Wouter Jukema*
Netherlands (1191)
Harvey White
New Zealand (164)
Terje Pedersen
Norway (295)
Frank Britto
Peru (66)
Witold Ruzyllo
Poland (589)
Manuel Carrageta
Portugal (102)
Ki-Bae Seung
S. Korea (118)
Singapore (75), Malaysia (59), Hong Kong (58) Ecuador (45), Taiwan (46)
*Steering Comm Member, ¹ Deceased, ² 2005–2013
Tibor Duris
Slovakia (121)
Anthony Dalby
S. Africa (186)
Jose Lopez-Sendon
Spain (551)
Mikael Dellborg
Sweden (480)
Francois Mach
Switzerland (263)
Sema Guneri
Turkey (50)
Alexander Parkhomenko
Ukraine (159)
Adrian Brady
United Kingdom (318)
Michael Blazing
Christopher Cannon
Christie Ballantyne*
James de Lemos*
Neal Kleiman*
Darren McGuire*
United States (5869)
Background:
Cholesterol Lowering
➢ Lowering LDL cholesterol (LDL-C) has been a mainstay
of cardiovascular prevention
➢ Evidence mostly from statin trials which show reduction
in morbidity and mortality
– High-dose statins further reduce non-fatal CV events
➢ To date, no lipid-modifying therapy added to statins has
been demonstrated to provide a clinical benefit
– Fibrates, niacin, CETP inhibitors
➢ Recent ACC/AHA Guidelines have emphasized use of
statin therapy
➢ Despite current therapies, patients remain at high risk
Ezetimibe: Background
➢ Ezetimibe inhibits Niemann-Pick C1-like 1 (NPC1L1)
protein
– located primarily on the epithelial brush border of
the GI tract
– resulting in reduced cholesterol absorption
➢ When added to statin, produces ~20% further
reduction in LDL-C
➢ Two recent human genetic analyses have correlated
polymorphisms in NPC1L1 with lower levels of LDL-C
and lower risk of CV events*
*MI Genetics Consortium Investigators NEJM 2014; online Nov 12; Ference BA et al AHA 2014
Goals
IMPROVE-IT: First large trial evaluating clinical
efficacy of combination EZ/Simva vs. simvastatin
(i.e., the addition of ezetimibe to statin therapy):
➢ Does lowering LDL-C with the non-statin agent
ezetimibe reduce cardiac events?
➢ “Is (Even) Lower (Even) Better?”
(estimated mean LDL-C ~50 vs. 65mg/dL)
➢ Safety of ezetimibe
Cannon CP AHJ 2008;156:826-32; Califf RM NEJM 2009;361:712-7; Blazing MA AHJ 2014;168:205-12
Patient Population
Inclusion Criteria:
➢ Hospitalization for STEMI, NSTEMI/UA < 10 days
➢ Age ≥ 50 years, and ≥ 1 high-risk feature:
– New ST chg, + troponin, DM, prior MI, PAD, cerebrovasc,
prior CABG > 3 years, multivessel CAD
➢ LDL-C 50-125 mg/dL (50–100 mg/dL if prior lipid-lowering Rx)
Major Exclusion Criteria:
➢ CABG for treatment of qualifying ACS
➢ Current statin Rx more potent than simva 40mg
➢ Creat Cl < 30mL/min, active liver disease
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
Follow-up Visit Day 30, every 4 months
Duration: Minimum 2 ½-year follow-up (at least 5250 events)
Primary Endpoint: CV death, MI, hospital admission for UA,
coronary revascularization (≥ 30 days after randomization), or stroke
N=18,144
Uptitrated to
Simva 80 mg
if LDL-C > 79
(adapted per
FDA label 2011)
Study Design
*3.2mM
**2.6mM
Cannon CP AHJ 2008;156:826-32; Califf RM NEJM 2009;361:712-7; Blazing MA AHJ 2014;168:205-12
90% power to detect
~9% difference
Study Metrics
Simva
(N=9077)
EZ/Simva
(N=9067)
Uptitration to Simva 80mg, % 27 6
Premature study drug D/C, % 42 42
Median follow-up, yrs 6.0 5.9
Withdraw consent w/o vital status, %/yr 0.6 0.6
Lost to follow-up, %/yr 0.10 0.09
Follow up for primary endpoint, % 91 91
Follow up for survival, % 97 97
Total primary endpoint events = 5314
Total patient-years clinical follow-up = 97,822
Total patient-years follow-up for survival = 104,135
Baseline Characteristics
Simvastatin
(N=9077)
%
EZ/Simva
(N=9067)
%
Age (years) 64 64
Female 24 25
Diabetes 27 27
MI prior to index ACS 21 21
STEMI / NSTEMI / UA 29 / 47 / 24 29 / 47 / 24
Days post ACS to rand (IQR) 5 (3, 8) 5 (3, 8)
Cath / PCI for ACS event 88 / 70 88 / 70
Prior lipid Rx 35 36
LDL-C at ACS event (mg/dL, IQR) 95 (79, 110) 95 (79,110)
LDL-C and Lipid Changes
1 Yr Mean LDL-C TC TG HDL hsCRP
Simva 69.9 145.1 137.1 48.1 3.8
EZ/Simva 53.2 125.8 120.4 48.7 3.3
Δ in mg/dL -16.7 -19.3 -16.7 +0.6 -0.5
Median Time avg
69.5 vs. 53.7 mg/dL
Primary Endpoint — ITT
Simva — 34.7%
2742 events
EZ/Simva — 32.7%
2572 events
HR 0.936 CI (0.887, 0.988)
p=0.016
Cardiovascular death, MI, documented unstable angina requiring
rehospitalization, coronary revascularization (≥30 days), or stroke
7-year event rates
NNT= 50
Simva* EZ/Simva* p-value
Primary 34.7 32.7 0.016
CVD/MI/UA/Cor Revasc/CVA
Secondary #1 40.3 38.7 0.034
All D/MI/UA/Cor Revasc/CVA
Secondary #2 18.9 17.5 0.016
CHD/MI/Urgent Cor Revasc
Secondary #3 36.2 34.5 0.035
CVD/MI/UA/All Revasc/CVA
0.936
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 — ITT
0.8 1.0 1.1
0.948
0.912
0.945
HR Simva* EZ/Simva* p-value
All-cause death 0.99 15.3 15.4 0.782
CVD 1.00 6.8 6.9 0.997
CHD 0.96 5.8 5.7 0.499
MI 0.87 14.8 13.1 0.002
Stroke 0.86 4.8 4.2 0.052
Ischemic stroke 0.79 4.1 3.4 0.008
Cor revasc ≥ 30d 0.95 23.4 21.8 0.107
UA 1.06 1.9 2.1 0.618
CVD/MI/stroke 0.90 22.2 20.4 0.003
Ezetimibe/Simva
Better
Simva
Better
Individual Cardiovascular
Endpoints and CVD/MI/Stroke
0.6 1.0 1.4
*7-year
event rates (%)
Simva — 22.2%
1704 events
EZ/Simva — 20.4%
1544 events
HR 0.90 CI (0.84, 0.97)
p=0.003
NNT= 56
CV Death, Non-fatal MI,
or Non-fatal Stroke
7-year event rates
Simva† EZ/Simva†
Male 34.9 33.3
Female 34.0 31.0
Age < 65 years 30.8 29.9
Age ≥ 65 years 39.9 36.4
No diabetes 30.8 30.2
Diabetes 45.5 40.0
Prior LLT 43.4 40.7
No prior LLT 30.0 28.6
LDL-C > 95 mg/dl 31.2 29.6
LDL-C ≤ 95 mg/dl 38.4 36.0
Major Pre-specified
Subgroups
Ezetimibe/Simva
Better
Simva
Better
0.7 1.0 1.3
†7-year
event rates
*
*p-interaction = 0.023, otherwise > 0.05
IMPROVE-IT vs. CTT:
Ezetimibe vs. Statin Benefit
CTT Collaboration.
Lancet 2005; 366:1267-78;
Lancet 2010;376:1670-81.
IMPROVE-IT
Safety — ITT
No statistically significant differences in cancer or
muscle- or gallbladder-related events
Simva
n=9077
%
EZ/Simva
n=9067
% p
ALT and/or AST≥3x ULN 2.3 2.5 0.43
Cholecystectomy 1.5 1.5 0.96
Gallbladder-related AEs 3.5 3.1 0.10
Rhabdomyolysis* 0.2 0.1 0.37
Myopathy* 0.1 0.2 0.32
Rhabdo, myopathy, myalgia with CK elevation* 0.6 0.6 0.64
Cancer* (7-yr KM %) 10.2 10.2 0.57
* Adjudicated by Clinical Events Committee % = n/N for the trial duration
Conclusions
IMPROVE-IT: First trial demonstrating incremental
clinical benefit when adding a non-statin agent
(ezetimibe) to statin therapy:
YES: Non-statin lowering LDL-C with ezetimibe
reduces cardiovascular events
YES: Even Lower is Even Better
(achieved mean LDL-C 53 vs. 70 mg/dL at 1 year)
YES: Confirms ezetimibe safety profile
Reaffirms the LDL hypothesis, that reducing
LDL-C prevents cardiovascular events
Results could be considered for future guidelines

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Improve it

  • 1. IMProved Reduction of Outcomes: Vytorin Efficacy International Trial A Multicenter, Double-Blind, Randomized Study to Establish the Clinical Benefit and Safety of Vytorin (Ezetimibe/Simvastatin Tablet) vs Simvastatin Monotherapy in High-Risk Subjects Presenting With Acute Coronary Syndrome
  • 2. Trial Leadership Study Chairmen: Eugene Braunwald and Robert Califf TIMI Study Group: Christopher Cannon Robert Giugliano Amy McCagg Christina Pelland Sabina Murphy Erin Bohula May DCRI: Michael Blazing Craig Reist Jennifer White Yuliya Lokhnygina Curtis Campbell Cathy Martz Merck: Thomas Musliner Andrew Tershakovec Ann Kilian Rona Harmelin-Kadouri Paul DeLucca Steve Bird DSMB Chair: Scott Grundy CEC Chair: Stephen Wiviott
  • 3. National Lead Investigators and Steering Committee (1158 sites, 39 Countries) Enrique Gurfinkel¹ Argentina (331) Philip Aylward Andrew Tonkin* Australia (116) Gerald Maurer Austria (249) Frans Van de Werf Belgium (249) Jose C. Nicolau Brazil (423) Pierre Theroux Paul Armstrong* Jacques Genest* Canada (1106) Ramon Cobalan Chile (152) Daniel Isaza Colombia (568) Jindrich Spinar Czech Rep (371) Peer Grande² Denmark (576) Juri Voitk Estonia (10) Antero Kesaniemi Finland (341) Jean-Pierre Bassand Michel Farnier* France (268) Harald Darius Germany (935) Matayas Keltai Hungary (116) Atul Mathur Sanjay Mittal Krishna Reddy India (259) Basil Lewis Israel (589) Gaetano DeFerrari Italy (593) Ton Oude Ophuis J. Wouter Jukema* Netherlands (1191) Harvey White New Zealand (164) Terje Pedersen Norway (295) Frank Britto Peru (66) Witold Ruzyllo Poland (589) Manuel Carrageta Portugal (102) Ki-Bae Seung S. Korea (118) Singapore (75), Malaysia (59), Hong Kong (58) Ecuador (45), Taiwan (46) *Steering Comm Member, ¹ Deceased, ² 2005–2013 Tibor Duris Slovakia (121) Anthony Dalby S. Africa (186) Jose Lopez-Sendon Spain (551) Mikael Dellborg Sweden (480) Francois Mach Switzerland (263) Sema Guneri Turkey (50) Alexander Parkhomenko Ukraine (159) Adrian Brady United Kingdom (318) Michael Blazing Christopher Cannon Christie Ballantyne* James de Lemos* Neal Kleiman* Darren McGuire* United States (5869)
  • 4. Background: Cholesterol Lowering ➢ Lowering LDL cholesterol (LDL-C) has been a mainstay of cardiovascular prevention ➢ Evidence mostly from statin trials which show reduction in morbidity and mortality – High-dose statins further reduce non-fatal CV events ➢ To date, no lipid-modifying therapy added to statins has been demonstrated to provide a clinical benefit – Fibrates, niacin, CETP inhibitors ➢ Recent ACC/AHA Guidelines have emphasized use of statin therapy ➢ Despite current therapies, patients remain at high risk
  • 5. Ezetimibe: Background ➢ Ezetimibe inhibits Niemann-Pick C1-like 1 (NPC1L1) protein – located primarily on the epithelial brush border of the GI tract – resulting in reduced cholesterol absorption ➢ When added to statin, produces ~20% further reduction in LDL-C ➢ Two recent human genetic analyses have correlated polymorphisms in NPC1L1 with lower levels of LDL-C and lower risk of CV events* *MI Genetics Consortium Investigators NEJM 2014; online Nov 12; Ference BA et al AHA 2014
  • 6. Goals IMPROVE-IT: First large trial evaluating clinical efficacy of combination EZ/Simva vs. simvastatin (i.e., the addition of ezetimibe to statin therapy): ➢ Does lowering LDL-C with the non-statin agent ezetimibe reduce cardiac events? ➢ “Is (Even) Lower (Even) Better?” (estimated mean LDL-C ~50 vs. 65mg/dL) ➢ Safety of ezetimibe Cannon CP AHJ 2008;156:826-32; Califf RM NEJM 2009;361:712-7; Blazing MA AHJ 2014;168:205-12
  • 7. Patient Population Inclusion Criteria: ➢ Hospitalization for STEMI, NSTEMI/UA < 10 days ➢ Age ≥ 50 years, and ≥ 1 high-risk feature: – New ST chg, + troponin, DM, prior MI, PAD, cerebrovasc, prior CABG > 3 years, multivessel CAD ➢ LDL-C 50-125 mg/dL (50–100 mg/dL if prior lipid-lowering Rx) Major Exclusion Criteria: ➢ CABG for treatment of qualifying ACS ➢ Current statin Rx more potent than simva 40mg ➢ Creat Cl < 30mL/min, active liver disease
  • 8. 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 Follow-up Visit Day 30, every 4 months Duration: Minimum 2 ½-year follow-up (at least 5250 events) Primary Endpoint: CV death, MI, hospital admission for UA, coronary revascularization (≥ 30 days after randomization), or stroke N=18,144 Uptitrated to Simva 80 mg if LDL-C > 79 (adapted per FDA label 2011) Study Design *3.2mM **2.6mM Cannon CP AHJ 2008;156:826-32; Califf RM NEJM 2009;361:712-7; Blazing MA AHJ 2014;168:205-12 90% power to detect ~9% difference
  • 9. Study Metrics Simva (N=9077) EZ/Simva (N=9067) Uptitration to Simva 80mg, % 27 6 Premature study drug D/C, % 42 42 Median follow-up, yrs 6.0 5.9 Withdraw consent w/o vital status, %/yr 0.6 0.6 Lost to follow-up, %/yr 0.10 0.09 Follow up for primary endpoint, % 91 91 Follow up for survival, % 97 97 Total primary endpoint events = 5314 Total patient-years clinical follow-up = 97,822 Total patient-years follow-up for survival = 104,135
  • 10. Baseline Characteristics Simvastatin (N=9077) % EZ/Simva (N=9067) % Age (years) 64 64 Female 24 25 Diabetes 27 27 MI prior to index ACS 21 21 STEMI / NSTEMI / UA 29 / 47 / 24 29 / 47 / 24 Days post ACS to rand (IQR) 5 (3, 8) 5 (3, 8) Cath / PCI for ACS event 88 / 70 88 / 70 Prior lipid Rx 35 36 LDL-C at ACS event (mg/dL, IQR) 95 (79, 110) 95 (79,110)
  • 11. LDL-C and Lipid Changes 1 Yr Mean LDL-C TC TG HDL hsCRP Simva 69.9 145.1 137.1 48.1 3.8 EZ/Simva 53.2 125.8 120.4 48.7 3.3 Δ in mg/dL -16.7 -19.3 -16.7 +0.6 -0.5 Median Time avg 69.5 vs. 53.7 mg/dL
  • 12. Primary Endpoint — ITT Simva — 34.7% 2742 events EZ/Simva — 32.7% 2572 events HR 0.936 CI (0.887, 0.988) p=0.016 Cardiovascular death, MI, documented unstable angina requiring rehospitalization, coronary revascularization (≥30 days), or stroke 7-year event rates NNT= 50
  • 13. Simva* EZ/Simva* p-value Primary 34.7 32.7 0.016 CVD/MI/UA/Cor Revasc/CVA Secondary #1 40.3 38.7 0.034 All D/MI/UA/Cor Revasc/CVA Secondary #2 18.9 17.5 0.016 CHD/MI/Urgent Cor Revasc Secondary #3 36.2 34.5 0.035 CVD/MI/UA/All Revasc/CVA 0.936 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 — ITT 0.8 1.0 1.1 0.948 0.912 0.945
  • 14. HR Simva* EZ/Simva* p-value All-cause death 0.99 15.3 15.4 0.782 CVD 1.00 6.8 6.9 0.997 CHD 0.96 5.8 5.7 0.499 MI 0.87 14.8 13.1 0.002 Stroke 0.86 4.8 4.2 0.052 Ischemic stroke 0.79 4.1 3.4 0.008 Cor revasc ≥ 30d 0.95 23.4 21.8 0.107 UA 1.06 1.9 2.1 0.618 CVD/MI/stroke 0.90 22.2 20.4 0.003 Ezetimibe/Simva Better Simva Better Individual Cardiovascular Endpoints and CVD/MI/Stroke 0.6 1.0 1.4 *7-year event rates (%)
  • 15. Simva — 22.2% 1704 events EZ/Simva — 20.4% 1544 events HR 0.90 CI (0.84, 0.97) p=0.003 NNT= 56 CV Death, Non-fatal MI, or Non-fatal Stroke 7-year event rates
  • 16. Simva† EZ/Simva† Male 34.9 33.3 Female 34.0 31.0 Age < 65 years 30.8 29.9 Age ≥ 65 years 39.9 36.4 No diabetes 30.8 30.2 Diabetes 45.5 40.0 Prior LLT 43.4 40.7 No prior LLT 30.0 28.6 LDL-C > 95 mg/dl 31.2 29.6 LDL-C ≤ 95 mg/dl 38.4 36.0 Major Pre-specified Subgroups Ezetimibe/Simva Better Simva Better 0.7 1.0 1.3 †7-year event rates * *p-interaction = 0.023, otherwise > 0.05
  • 17. IMPROVE-IT vs. CTT: Ezetimibe vs. Statin Benefit CTT Collaboration. Lancet 2005; 366:1267-78; Lancet 2010;376:1670-81. IMPROVE-IT
  • 18. Safety — ITT No statistically significant differences in cancer or muscle- or gallbladder-related events Simva n=9077 % EZ/Simva n=9067 % p ALT and/or AST≥3x ULN 2.3 2.5 0.43 Cholecystectomy 1.5 1.5 0.96 Gallbladder-related AEs 3.5 3.1 0.10 Rhabdomyolysis* 0.2 0.1 0.37 Myopathy* 0.1 0.2 0.32 Rhabdo, myopathy, myalgia with CK elevation* 0.6 0.6 0.64 Cancer* (7-yr KM %) 10.2 10.2 0.57 * Adjudicated by Clinical Events Committee % = n/N for the trial duration
  • 19. Conclusions IMPROVE-IT: First trial demonstrating incremental clinical benefit when adding a non-statin agent (ezetimibe) to statin therapy: YES: Non-statin lowering LDL-C with ezetimibe reduces cardiovascular events YES: Even Lower is Even Better (achieved mean LDL-C 53 vs. 70 mg/dL at 1 year) YES: Confirms ezetimibe safety profile Reaffirms the LDL hypothesis, that reducing LDL-C prevents cardiovascular events Results could be considered for future guidelines