Table F-3

Surrogate outcome – LDL-c using ezetimibe plus statin therapy compared with statin monotherapy

Low density lipoprotein cholesterol
TrialPopulationCombination Statin Dose (mg/day)Combo NMonotherapy Statin Dose (mg/day)Mono NFollow- up (wk)Mean Baseline LDL-c (mg/dL)Combo- mono: mean difference (95% CI) mg/dLAACJadad ScoreITTA
Combination – monotherapy, difference in mean percentage change from baseline (%): all statins, all doses, all clinical populations
Kastelein (2008)42
ENHANCE International Pharm. fund
FHC, LDL-c > 210 mg/dLSimvastatin 80357Simvastatin 8036396318−16.50 (−16.63, −16.37)Adequate3no
Ballantyne (2003)126
Ezetimibe Study Group International Pharm. Fund Multicenter
HC, heterogeneous 10-year CHD risk estimatesAtorvastatin 80201Atorvastatin 804552183−10.00 (−15.76, −4.24)unclear2no
Ballantyne (2004_b)46
North America Pharm. Fund Multicenter
HC, heterogeneous 10-year CHD risk estimatesSimvastatin 80432Atorvastatin 8022324180−6.90 (−9.27, −4.53)unclear3no
Landray (2006)166
UK-HARP-II Europe Pharm. Fund Multicenter
Participants with renal disease and without definitive indication for cholesterol loweringSimvastatin 20102simvastatin 2010124119−21.00 (−30.74, −11.26)Adequate2no
Gaudiani (2005)121
North America Pharm. Fund Multicenter
Participants with T2DM on stable thiazolidinediones, some of whom had previously completed a simvastatin trial, with LDL-c > 100 mg/dLSimvastatin 20103Simvastatin 401076–2493−20.50 (−26.60, −14.40)unclear3no
Bays (2004)154
North America Pharm. Fund Multicenter
1 ° HC, heterogeneous 10-year CHD risk estimatesSimvastatin 10–80539Simvastatin 10–805596–26178−14.90 (−16.46, −13.34)Adequate5no
Berthold (2006)109
Europe Pharm. Fund Single centre
Healthy male participants. Low riskSimvastatin 4024Simvastatin 40242–3114−18.90 (−24.97, −12.83)unclear2yes
Stein (2004)156
International Pharm. fund
LDL >= 130 mg/dL despite diet and atorvastatin 10 mg/dayAtorvastatin 40278Atorvastatin 8029014186−13.60 (−16.10, −11.10)unclear3yes
Rodney (2006)111
Pharm. Fund Multicenter
African descent, 1° HCSimvastatin 20124Simvastatin 2012312176−17.20 (−21.13, −13.27)Adequate5no
Masana (2005)167
Ezetimibe study group International Pharm. fund
Participants on stable statin treatment but not on ATP II LDL-c goalsSimvastatin 80344Simvastatin 807812136−27.00 (−34.80, −19.20)unclear3no
Goldberg (2004)48
Ezetimibe Study Group International Pharm. fund
statin naïve, 1 ° HC, heterogeneous 10-year CHD risk estimatesSimvastatin 10–80323Simvastatin 10–8032212175−14.70 (−17.13, −12.27)Adequate5no
Melani (2003)127
Ezetimibe Study Group North America Pharm. Fund Multicenter
HC, heterogeneous 10- year CHD risk estimatesPravastatin 10–40204Pravastatin 10–4020512178−13.40 (−15.89, −10.91)Adequate4yes
Kerzner (2003)129
Ezetimibe Study Group North America Pharm. Fund Multicenter
HC, heterogeneous 10-year CHD risk estimatesLovastatin 10–40181Lovastatin 10–4020212179−15.00 (−17.78, −12.22)unclear3yes
Davidson (2002)130
Ezetimibe study group North America Pharm. Fund Multicenter
HC, heterogeneous 10-year CHD risk estimatesSimvastatin 10–80253Simvastatin 10–8024912179−15.20 (−17.70, −12.70)Adequate4no
Gagne (2002_1)132
Ezetimibe Study Group International Pharm. fund
Homozygous FHC, 7 (14%) participants between 12–18 years of ageAtorvastatin 8012Atorvastatin 801212309−21.16 (−30.97, −11.35)unclear3no
Gagne (2002_2)132
Ezetimibe Study Group International Pharm. fund
Homozygous FHC, 7 (14%) participants between 12–18 years of ageSimvastatin 805Simvastatin 80512309−18.83 (−36.43, −1.23)unclear3no
McKenney (2007_1)139
COMPELL study North America Pharm. Fund Multicenter
HC, heterogeneous 10-year CHD risk estimatesSimvastatin 4072Rosuvastatin407312197−4.00 (−8.95, 0.95)unclear2no
Shankar (2007)168
Asia Pharm. Fund Multicenter
South Asians, heterogeneous 10-year CHD risk estimatesSimvastatin 10114Simvastatin 1011612127−7.40 (−16.33, 1.53)unclear2yes
Masana (2005)167
Ezetimibe study group International Pharm. fund
Participants on stable statin treatment but not on ATP II LDL-c goals, subgroup with DMMixed 10–8088Mixed 10–80948136−26.10 (−30.69, −21.51)unclear3no
Barrios (2005)112
International Pharm. fund
CHD or risk equivalentSimvastatin 20215Atorvastatin 202076124−12.50 (−15.83, −9.17)unclear35no
Farnier (2005)114 International Pharm. Fund MulticenterParticipants with CAD on low dose simvastatinSimvastatin 10–20102Simvastatin 10–201016123−24.30 (−27.78, −20.82)unclear5no
Cruz-Fernandez (2005)115
International Pharm. Fund Multicenter
Participants with CAD on low dose atorvastatinAtorvastatin 10–20219Atorvastatin 10–202246122−26.90 (−29.80, − 24.00)unclear4no
Brohet (2005)116
Europe Pharm. Fund Multicenter
Participants with CAD on low dose simvastatinSimvastatin 10–20204Simvastatin 10–202076123−23.00 (−25.86, − 20.14)unclear5no
Pearson (2005)117
EASE North America Pharm. Fund Multicenter
Participants not meeting ATP III target LDL-c despite statin therapyMixed1940Mixed9686129−23.10 (−24.45, −21.75)Adequate4no
Pearson (2005)117
EASE North America Pharm. Fund Multicenter
Participants not meeting ATP III target LDL-c despite statin therapy, African descent subgroupSimvastatin 20174Simvastatin 20936129−23.00 (−27.55, − 18.45)Adequate4no
Pearson (2005)117
EASE North America Pharm. Fund Multicenter
Participants not meeting ATP III target LDL-c despite statin therapy, Hispanic subgroupMixed94Mixed536129−21.10 (−27.16, −15.04)Adequate4no
Ballantyne (2005_1)118
VYVA North America Pharm. Fund Multicenter
Participants not on ATP III target LDL-cSimvastatin 20233Atorvastatin 202306178−6.90 (−9.49, −4.31)Adequate2no
Ballantyne (2005_2)118
VYVA North America Pharm. Fund Multicenter
Participants not on ATP III target LDL-cSimvastatin 40236Atorvastatin 402326178−9.10 (−11.69, −6.51)Adequate2no
Ballantyne (2005_3)118
VYVA North America Pharm. Fund Multicenter
Participants not on ATP III target LDL-cSimvastatin 80224Atorvastatin 802306178−5.70 (−8.39, −3.01)Adequate2no
Blagden (2007)140
Europe Pharm. Fund Multicenter
Participants with CAD, statin naïveAtorvastatin 1072Atorvastatin 10766157−14.10 (−17.92, −10.28)unclear4yes
Ballantyne (2007)142
Europe Pharm. Fund Multicenter
CHD and risk equivalentRosuvastatin 40235Rosuvastatin 402306190−24.60 (−29.39, −19.81)unclear1no
Patel (2006)143
Europe Pharm. Fund Multicenter
Participants with CAD not on recent lipid lowering drug treatmentSimvastatin 2072Simvastatin 20716160−14.60 (−19.06, −10.14)unclear3no
Goldberg (2006_1)144
VYTAL North America Pharm. Fund Multicenter
T2DM, hemoglobin A-1c < 8.5% and LDL-c > 100 mg/dLSimvastatin 20238Atorvastatin 202406145−9.00 (-11.55, -6.45)Adequate3
Goldberg (2006_2)144
VYTAL North America Pharm. Fund Multicenter
T2DM, hemoglobin A-1c < 8.5% and LDL-c > 100 mg/dLSimvastatin 40242Atorvastatin 402416145−6.70 (−9.25, −4.15)Adequate3no
Catapano (2006)193
North America Pharm. Fund Multicenter
Hypercholesterole mia, heterogeneous 10- year CHD risk estimatesSimvastatin 20–801427Rosuvastatin 10–4014286173−4.20 (−5.03, −3.37)Adequate3no
Constance (2007)194
International Pharm. fund
Participants with T2DM on low dose atorvastatinSimvastatin 20210Atorvastatin 20213694−17.66 (−22.78, −12.54)Adequate3no
Feldman (2004)47
North America Pharm. Fund Multicenter
Participants with CHD or risk equivalentSimvastatin 4097Simvastatin 4024823169−14.00 (−17.53, −10.47)unclear2no
Kosoglou (2004)124
Europe Pharm. Fund Single centre
Healthy participants with LDL-c >= 130 mg/dL and BMI < 31kg/m2. Low riskRosuvastatin 1012Rosuvastatin 10112158−15.90 (−22.16, −9.64)unclear2yes
Gouni-Berthold (2008)110
Europe Pharm. Fund Single
Healthy males with LDL-c < 190 mg/dL and < 60 years of age, previously not on lipid lowering treatmentSimvastatin 4024Simvastatin 40242114.5−18.90 (−24.97, − 12.83)Unclear2Yes
Conrad (2008)158
International Pharm. Fund Multicenter
Moderately high risk participants on atorvastatin 20 mg/day or statin naive and with LDL-c 100 mg/dL to <= 160 mg/dLAtorvastatin 2092Atorvastatin 40926119−19.90 (−25.17, −14.63)Adequate5No
Dobs (2003)169
Pharm. Fund Multicenter
Participants of mixed 10 year CHD risk, with primary hyperlipidemia (LDL-c >=130 mg/dL) not controlled on simvastatin 20 mg/daySimvastatin 2066Simvastatin 40344169−13.36 (−18.31, −8.41)Adequate5Yes
Leiter (2008)159
North America Pharm. Fund Multicenter
Participants with or without prior lipid lowering therapy with 10-year CHD risk > 20%Atorvastatin 40277Atorvastatin 80279689−16.40 (−19.45, −13.35)Adequate5No
Combination – monotherapy, difference in mean percentage change from baseline (%):all statins, lower versus higher doses, all clinical populations
Gaudiani (2005)121
North America Pharm. Fund Multicenter
Participants with T2DM on stable thiazolidinediones, some of whom had previously completed a simvastatin trial, with LDL-c > 100 mg/dLSimvastatin 20103Simvastatin 401076–2493−20.50 (−26.60, − 14.40)unclear3no
Bays (2004_1)154
North America Pharm. Fund Multicenter
HC, heterogeneous 10- year CHD risk estimatesSimvastatin 10222Simvastatin 401086–26178−5.90 (−8.80, −3.00)Adequate5no
Bays (2004_2)154
North America Pharm. Fund Multicenter
HC, heterogeneous 10- year CHD risk estimatesSimvastatin 20106Simvastatin 802246–26178−3.00 (−5.93, −0.07)Adequate5no
Feldman (2004)47
North America Pharm. Fund Multicenter
Participants with CHD or risk equivalentSimvastatin 20109Simvastatin 4024823169−10.00 (−13.19, −6.81)unclear2no
Goldberg (2004_1)48
Ezetimibe Study Group International Pharm. fund
statin naïve, 1° HC, heterogeneous 10-year CHD risk estimatesSimvastatin 1087Simvastatin 409012175−4.70 (−8.19, −−0.49)Adequate5no
Goldberg (2004_2)48
Ezetimibe Study Group International Pharm. fund
statin naïve, 1° HC, heterogeneous 10- year CHD risk estimatesSimvastatin 2086Simvastatin 808712175−4.90 (−9.21, −0.59)Adequate5no
Davidson (2002_1)130
Ezetimibe study group North America Pharm. Fund Multicenter
HC, heterogeneous 10-year CHD risk estimatesSimvastatin 1067Simvastatin 406412179−8.12 (−13.03, −3.21)Adequate4no
Davidson (2002_2)130
Ezetimibe study group North America Pharm. Fund Multicenter
HC, heterogeneous 10- year CHD risk estimatesSimvastatin 2068Simvastatin 806612179−0.53 (−5.39, −4.33)Adequate4no
Dobs (2003)169
Pharm. Fund Multicenter
Participants of mixed 10 year CHD risk, with primary hyperlipidemia (LDL-c >=130 mg/dL) not controlled on simvastatin 20 mg/daySimvastatin 2066Simvastatin 40344169−13.36 (−18.31, −8.41)Adequate5Yes
Combination – monotherapy, difference in mean percentage change from baseline (%):all statins, all doses, intensive lipid lowering populations and clinical subgroups
Barrios (2005)112 International Pharm. fundCHD or risk equivalentSimvastatin 20215Atorvastatin 202076124−12.50 (−15.83, −9.17)unclear3no
Farnier (2005)114
International Pharm. Fund Multicenter
Participants with CAD on low dose simvastatinSimvastatin 10–20102Simvastatin 10–201016123−24.30 (−27.78, − 20.82)unclear5no
Cruz-Fernandez (2005)115
International Pharm. Fund Multicenter
Participants with CAD on low dose atorvastatinAtorvastatin 10–20219Atorvastatin 10–202246122−26.90 (−29.80, − 24.00)unclear4no
Brohet (2005)116
Europe Pharm. Fund Multicenter
Participants with CAD on low dose simvastatinSimvastatin 10–20204Simvastatin 10–202076123−23.00 (−25.86, − 20.14)unclear5no
Masana (2005)167
Ezetimibe study group International Pharm. fund
Participants on stable statin treatment but not on ATP II LDL-c goals, subgroup with DMMixed 10–8088Mixed 10–80948136−26.10 (−30.69, − 21.51)unclear3no
Gaudiani (2005)121
North America Pharm. Fund Multicenter
Participants with T2DM on stable thiazolidinediones, some of whom had previously completed a simvastatin trial, with LDL-c > 100 mg/dLSimvastatin 20103Simvastatin 401076–2493−20.50 (−26.60, − 14.40)unclear3no
Feldman (2004)47
North America Pharm. Fund Multicenter
Participants with CHD or risk equivalentSimvastatin 40186Simvastatin 4018123169−14.00 (−17.53, −10.47)unclear2no
Gagne (2002_2)132
Ezetimibe Study Group International Pharm. fund
Homozygous FHC, 7 (14%) participants between 12–18 years of ageSimvastatin 805Simvastatin 80512309−18.83 (−36.43, −1.23)unclear3no
Blagden (2007)140
Europe Pharm. Fund Multicenter
Participants with CAD, statin naïveAtorvastatin 1072Atorvastatin 10766157−14.10 (−17.92, − 10.28)unclear4yes
Ballantyne (2007)142
Europe Pharm. Fund Multicenter
CHD and risk equivalentRosuvastatin 40235Rosuvastatin 402306190−24.60 (−29.39, − 19.81)unclear1no
Patel (2006)143
Europe Pharm. Fund Multicenter
Participants with CAD not on recent lipid lowering drug treatmentSimvastatin 2072Simvastatin 20716160−14.60 (−19.06, − 10.14)unclear3no
Goldberg (2006_2)144
VYTAL North America Pharm. Fund Multicenter
T2DM, hemoglobin A-1c < 8.5% and LDL-c > 100 mg/dLSimvastatin 40242Atorvastatin 402416145−6.70 (−9.25, −4.15)Adequate3no
Constance (2007)194
International Pharm. fund
Participants with T2DM on low dose atorvastatinSimvastatin 20210Atorvastatin 20213694−17.66 (−22.78, − 12.54)Adequate3no
Kastelein (2008)42
ENHANCE International Pharm. fund
FHC, LDL-c > 210 mg/dLSimvastatin 80357Simvastatin 8036396318−16.50 (−16.63, − 16.37)Adequate3no
Ballantyne (2005)118
VYVA North America Pharm. Fund Multicenter
Participants with DM not at LDL-c ATP III goal off lipid lowering treatmentSimvastatin 10–80212Atorvastatin 10–802016178−10.20 (−13.25, −7.15)Adequate2no
Bays (2004)154
North America Pharm. Fund Multicentre
Mixed 10 years CHD risk participants who were protocol compliant in a previous base studySimvastatin 10–8086Simvastatin 10–80696–26178−9.40 (−13.62, − 5.18)Adequate5No
Catapno (2006)193
North America Pharm. Fund Multicenter
Participants with DMSimvastatin 20–80186Rosuvastatin 10–401816173−4.30 (−6.79, − 1.81)Adequate3No
Leiter (2008)159
North America Pharm. Fund Multicenter
Participants with or without prior lipid lowering therapy with 10-year CHD risk > 20%Atorvastatin 40277Atorvastatin 80279689−16.40 (−19.45, −13.35)Adequate5No
Bays (2004)154
North America Pharm. Fund Multicentre
Participants with DMSimvastatin 10–8034Simvastatin 10–80376–26178−14.40 (−21.18, −7.62)Adequate5No
Rodney (2006)111
Pharm. Fund Multicentre
African descent, 1° HCSimvastatin 20124Simvastatin 2012412176−17.2 (−21.1, − 13.27)Adequate5No
Farnier (2005)114
International Pharm. Fund Multicentre
Participants with CAD on low dose simvastatin -- African descentSimvastatin 10–201Simvastatin 10–2016111NAunclear5No
Pearson (2005)117
EASE North America Pharm. Fund Multicentre
Participants not meeting ATP III target LDL-c despite statin therapy -- African descentMixed174Mixed936129−23 (−27.5, − 18.45)Adequate4No
Bays (2004)154
North America Pharm. Fund Multicentre
Participants with CHDSimvastatin 10–8034Simvastatin 10–80376–26180−9.40 (−13.62, − 5.18)Adequate5No
Farnier (2005)114
International Pharm. Fund Multicentre
Participants with CAD on low dose simvastatin – Females onlySimvastatin 10–2056Simvastatin 10–20576111−23.99 (−30.53, −17.45)unclear5No
Davidson (2002)130
Ezetimibe study group North America Pharm. Fund Multicenter
HC, heterogeneous 10- year CHD risk estimates -- Females onlySimvastatin 10–80152Simvastatin 10–801471217913.4 (9.87, 16.93)Adequate4no
Dobs (2003)169
Pharm. Fund Multicenter
HC, heterogeneous 10- year CHD risk estimates, with (LDL-c >=130 mg/dL) not controlled on simvastatin 20 mg/day -- Females only,Simvastatin 2029Simvastatin 40154169−14.46 (−21.90, −7.02)Adequate5Yes
Pearson (2005)117
EASE North America Pharm. Fund Multicenter
Participants not meeting ATP III target LDL-c despite statin therapy, Hispanic subgroupMixed94Mixed536129−21.10 (−27.16, − 15.04)Adequate4no
Gagne
(2002_1)132 Ezetimibe Study Group International Pharm. fund
Homozygous FHC, 7 (14%) participants between 12–18 years of age – LDL > 190Atorvastatin 8012Atorvastatin 801212309−21.16 (−30.97, − 11.35)unclear3no
Gagne
(2002_2)132 Ezetimibe Study Group International Pharm. fund
Homozygous FHC, 7 (14%) participants between 12–18 years of age, LDL > 190Simvastatin 805Simvastatin 80512309−18.83 (−36.43, −1.23)unclear3no
Kastelein (2008)42
ENHANCE International Pharm. fund
FHC, LDL-c > 210 mg/dLSimvastatin 80357Simvastatin 8036396318−16.50 (−16.63, − 16.37)Adequate3no
Combination – monotherapy, difference in mean percentage change from baseline (%):all statins, lower versus higher doses, intensive lipid lowering populations and clinical subgroups
Gaudiani (2005)121
North America Pharm. Fund Multicenter
Participants with T2DM on stable thiazolidinediones, some of whom had previously completed a simvastatin trial, with LDL-c > 100 mg/dLSimvastatin 20103Simvastatin 401076–2493−20.50 (−26.60, − 14.40)unclear3no
Bays
(2004_1)154 North America Pharm. Fund Multicenter
HC, heterogeneous 10- year CHD risk estimatesSimvastatin 10222Simvastatin 401086–26178−5.90 (−8.80, −3.00)Adequate5no
Bays (2004_2)154
North America Pharm. Fund Multicenter
HC, heterogeneous 10- year CHD risk estimatesSimvastatin 20106Simvastatin 802246–26178−3.00 (−5.93, −0.07)Adequate5no
Feldman (2004)47
North America Pharm. Fund Multicenter
Participants with CHD or risk equivalentSimvastatin 20109Simvastatin 4024823169−10.00 (−13.19, −6.81)unclear2no
Goldberg (2004_1)48
Ezetimibe Study Group International Pharm. fund
statin naïve, 1° HC, heterogeneous 10- year CHD risk estimatesSimvastatin 1087Simvastatin 409012175−4.70 (−8.19, −-0.49)Adequate5no
Goldberg (2004_2)48
Ezetimibe Study Group International Pharm. fund
statin naïve, 1° HC, heterogeneous 10- year CHD risk estimatesSimvastatin 2086Simvastatin 808712175−4.90 (−9.21, −0.59)Adequate5no
Davidson (2002_1)130
Ezetimibe study group North America Pharm. Fund Multicenter
HC, heterogeneous 10- year CHD risk estimatesSimvastatin 1067Simvastatin 406412179−8.12 (−13.03, −3.21)Adequate4no
Davidson (2002_2)130
Ezetimibe study group North America Pharm. Fund Multicenter
HC, heterogeneous 10- year CHD risk estimatesSimvastatin 2068Simvastatin 806612179−0.53 (−5.39, −4.33)Adequate4no
Dobs (2003)169
Pharm. Fund Multicenter
Participants of mixed 10 year CHD risk, with primary hyperlipidemia (LDL-c >=130 mg/dL) not controlled on simvastatin 20 mg/daySimvastatin 2066Simvastatin 40344169−13.36 (−18.31, −8.41)Adequate5Yes
Davidson (2002_1)130
Ezetimibe study group North America Pharm. Fund Multicenter
HC, heterogeneous 10- year CHD risk estimates -- Females onlySimvastatin 1036Simvastatin 403512179−9.80 (−16.05, − 3.55)Adequate4no
Davidson (2002_2)130
Ezetimibe study group North America Pharm. Fund Multicenter
HC, heterogeneous 10- year CHD risk estimates -- Females onlySimvastatin 2034Simvastatin 803712179−1.8 (9.70, 6.10)Adequate4no
Dobs (2003)169
Pharm. Fund Multicenter
HC, heterogeneous 10- year CHD risk estimates, with (LDL-c >=130 mg/dL) not controlled on simvastatin 20 mg/day -- Females only,Simvastatin 2029Simvastatin 40154169−14.46 (−21.90, −7.02)Adequate5Yes

From: Appendix F, Included Evidence

Cover of Comparative Effectiveness of Lipid-Modifying Agents
Comparative Effectiveness of Lipid-Modifying Agents [Internet].
Comparative Effectiveness Reviews, No. 16.
Sharma M, Ansari MT, Soares-Weiser K, et al.

NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.