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Efficacy and Safety of Alirocumab in High-Risk Patients With Clinical Atherosclerotic Cardiovascular Disease and/or Heterozygous Familial Hypercholesterolemia (from 5 Placebo-Controlled ODYSSEY Trials)

2018; Elsevier BV; Volume: 121; Issue: 8 Linguagem: Inglês

10.1016/j.amjcard.2017.12.040

ISSN

1879-1913

Autores

Peter A. McCullough, Christie M. Ballantyne, Santosh K. Sanganalmath, Gisle Langslet, Seth J. Baum, Prediman K. Shah, Andrew Koren, Jonas Mandel, Michael H. Davidson,

Tópico(s)

Pharmaceutical Economics and Policy

Resumo

Patients with previous atherosclerotic cardiovascular disease (ASCVD) and/or heterozygous familial hypercholesterolemia (HeFH) are at high risk of future cardiovascular events. Despite maximally tolerated doses of statins, many patients still have elevated low-density lipoprotein cholesterol (LDL-C) levels. We evaluated the efficacy and safety of alirocumab in patients with ASCVD and/or HeFH on a maximally tolerated dose of statin (rosuvastatin 20 or 40 mg, atorvastatin 40 or 80 mg, or simvastatin 80 mg, or lower doses with an investigator-approved reason) ± other lipid-lowering therapies from 5 placebo-controlled phase 3 trials (52 to 78 weeks). Patients with (n = 2,449) and without (n = 1,050) ASCVD were pooled from the FH I, FH II, HIGH FH, LONG TERM, and COMBO I trials. Patients with HeFH with (n = 575) and without ASCVD (n = 682) were pooled from all trials except COMBO I. High-intensity statins were utilized in 55.7% to 59.0% and in 72.4% to 87.6% of the ASCVD and the HeFH groups, respectively. Efficacy end points included LDL-C percent change from baseline to week 24 stratified by alirocumab dose. Mean baseline demographics and lipid levels were comparable in alirocumab- and placebo-treated patients. LDL-C reductions from baseline at week 24 ranged from 46.6% to 51.3% for alirocumab 75/150 mg and from 54.1% to 61.9% for alirocumab 150 mg in ASCVD and HeFH groups and were sustained for up to 78 weeks. LDL-C reductions with alirocumab were independent of ASCVD and/or HeFH status (interaction p value >0.05). Concordant results were observed for other lipids analyzed. The overall safety in the subgroups analyzed was similar in both treatment arms. Injection-site reactions were observed more frequently with alirocumab versus placebo. Patients with previous atherosclerotic cardiovascular disease (ASCVD) and/or heterozygous familial hypercholesterolemia (HeFH) are at high risk of future cardiovascular events. Despite maximally tolerated doses of statins, many patients still have elevated low-density lipoprotein cholesterol (LDL-C) levels. We evaluated the efficacy and safety of alirocumab in patients with ASCVD and/or HeFH on a maximally tolerated dose of statin (rosuvastatin 20 or 40 mg, atorvastatin 40 or 80 mg, or simvastatin 80 mg, or lower doses with an investigator-approved reason) ± other lipid-lowering therapies from 5 placebo-controlled phase 3 trials (52 to 78 weeks). Patients with (n = 2,449) and without (n = 1,050) ASCVD were pooled from the FH I, FH II, HIGH FH, LONG TERM, and COMBO I trials. Patients with HeFH with (n = 575) and without ASCVD (n = 682) were pooled from all trials except COMBO I. High-intensity statins were utilized in 55.7% to 59.0% and in 72.4% to 87.6% of the ASCVD and the HeFH groups, respectively. Efficacy end points included LDL-C percent change from baseline to week 24 stratified by alirocumab dose. Mean baseline demographics and lipid levels were comparable in alirocumab- and placebo-treated patients. LDL-C reductions from baseline at week 24 ranged from 46.6% to 51.3% for alirocumab 75/150 mg and from 54.1% to 61.9% for alirocumab 150 mg in ASCVD and HeFH groups and were sustained for up to 78 weeks. LDL-C reductions with alirocumab were independent of ASCVD and/or HeFH status (interaction p value >0.05). Concordant results were observed for other lipids analyzed. The overall safety in the subgroups analyzed was similar in both treatment arms. Injection-site reactions were observed more frequently with alirocumab versus placebo. Patients with a history of atherosclerotic cardiovascular disease (ASCVD) and/or heterozygous familial hypercholesterolemia (HeFH) are at increased risk of future ASCVD events.1Catapano A.L. Graham I. De Backer G. Wiklund O. Chapman M.J. Drexel H. Hoes A.W. Jennings C.S. Landmesser U. Pedersen T.R. Reiner Z. Riccardi G. Taskinen M.R. Tokgozoglu L. Verschuren W.M. Vlachopoulos C. Wood D.A. Zamorano J.L. Authors/Task Force Members, Additional Contributor2016 ESC/EAS guidelines for the management of dyslipidaemias.Eur Heart J. 2016; 37: 2999-3058Crossref PubMed Scopus (2042) Google Scholar, 2Stone N.J. Robinson J.G. Lichtenstein A.H. Bairey Merz C.N. Blum C.B. Eckel R.H. Goldberg A.C. Gordon D. Levy D. Lloyd-Jones D.M. McBride P. Schwartz J.S. Shero S.T. Smith Jr, S.C. Watson K. Wilson P.W. American College of Cardiology/American Heart Association Task Force on Practice Guidelines2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.J Am Coll Cardiol. 2014; 63: 2889-2934Crossref PubMed Scopus (3304) Google Scholar ASCVD has been defined as coronary heart disease, stroke, and peripheral arterial disease.2Stone N.J. Robinson J.G. Lichtenstein A.H. Bairey Merz C.N. Blum C.B. Eckel R.H. Goldberg A.C. Gordon D. Levy D. Lloyd-Jones D.M. McBride P. Schwartz J.S. Shero S.T. Smith Jr, S.C. Watson K. Wilson P.W. American College of Cardiology/American Heart Association Task Force on Practice Guidelines2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.J Am Coll Cardiol. 2014; 63: 2889-2934Crossref PubMed Scopus (3304) Google Scholar Consensus statements from major guideline committees3Landmesser U. John Chapman M. Farnier M. Gencer B. Gielen S. Hovingh G.K. Luscher T.F. Sinning D. Tokgozoglu L. Wiklund O. Zamorano J.L. Pinto F.J. Catapano A.L. European Society of Cardiology/European Atherosclerosis Society Task Force consensus statement on proprotein convertase subtilisin/kexin type 9 inhibitors: practical guidance for use in patients at very high cardiovascular risk.Eur Heart J. 2017; 38 (on behalf of the; European Society of Cardiology, European Atherosclerosis Society): 2245-2255PubMed Google Scholar, 4Lloyd-Jones D.M. Morris P.B. Ballantyne C.M. Birtcher K.K. Daly Jr, D.D. DePalma S.M. Minissian M.B. Orringer C.E. Smith Jr, S.C. 2016 ACC Expert Consensus Decision Pathway on the role of non-statin therapies for LDL-cholesterol lowering in the management of atherosclerotic cardiovascular disease risk: a report of the American College of Cardiology Task Force on Clinical Expert Consensus Documents.J Am Coll Cardiol. 2016; 68: 92-125Crossref PubMed Scopus (348) Google Scholar recommend that proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors may be considered in patients with HeFH or ASCVD who have elevated baseline low-density lipoprotein cholesterol (LDL-C) levels despite maximally tolerated statin with or without ezetimibe. The ODYSSEY phase 3 clinical trial program included 5 trials (LONG TERM, COMBO I, FH I, FH II, and HIGH FH) that compared alirocumab (a PCSK9 inhibitor) with placebo as add-on to maximally tolerated statin over 52 to 78 weeks, with most patients having previous ASCVD and/or HeFH.5Kastelein J.J. Ginsberg H.N. Langslet G. Hovingh G.K. Ceska R. Dufour R. Blom D. Civeira F. Krempf M. Lorenzato C. Zhao J. Pordy R. Baccara-Dinet M.T. Gipe D.A. Geiger M.J. Farnier M. ODYSSEY FH I and FH II: 78 week results with alirocumab treatment in 735 patients with heterozygous familial hypercholesterolaemia.Eur Heart J. 2015; 36: 2996-3003PubMed Google Scholar, 6Kereiakes D.J. Robinson J.G. Cannon C.P. Lorenzato C. Pordy R. Chaudhari U. Colhoun H.M. Efficacy and safety of the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab among high cardiovascular risk patients on maximally tolerated statin therapy: the ODYSSEY COMBO I study.Am Heart J. 2015; 169 (e13): 906-915Abstract Full Text Full Text PDF PubMed Scopus (279) Google Scholar, 7Robinson J.G. Farnier M. Krempf M. Bergeron J. Luc G. Averna M. Stroes E.S. Langslet G. Raal F.J. El Shahawy M. Koren M.J. Lepor N.E. Lorenzato C. Pordy R. Chaudhari U. Kastelein J.J.P. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events.N Engl J Med. 2015; 372: 1489-1499Crossref PubMed Scopus (1543) Google Scholar, 8Ginsberg H.N. Rader D.J. Raal F.J. Guyton J.R. Baccara-Dinet M.T. Lorenzato C. Pordy R. Stroes E. Efficacy and safety of alirocumab in patients with heterozygous familial hypercholesterolemia and LDL-C of 160 mg/dl or higher.Cardiovasc Drugs Ther. 2016; 30: 473-483Crossref PubMed Scopus (146) Google Scholar This analysis evaluated the efficacy and safety of alirocumab in patients with or without ASCVD or with HeFH (with or without ASCVD), thereby providing a comprehensive summary for clinicians in these 2 clinical conditions. Methods and primary results of the 5 ODYSSEY trials (n = 3,499) included in this analysis (FH I, NCT01623115; FH II, NCT01709500; LONG TERM, NCT01507831; HIGH FH, NCT01617655; and COMBO I, NCT01644175) have been reported previously.5Kastelein J.J. Ginsberg H.N. Langslet G. Hovingh G.K. Ceska R. Dufour R. Blom D. Civeira F. Krempf M. Lorenzato C. Zhao J. Pordy R. Baccara-Dinet M.T. Gipe D.A. Geiger M.J. Farnier M. ODYSSEY FH I and FH II: 78 week results with alirocumab treatment in 735 patients with heterozygous familial hypercholesterolaemia.Eur Heart J. 2015; 36: 2996-3003PubMed Google Scholar, 6Kereiakes D.J. Robinson J.G. Cannon C.P. Lorenzato C. Pordy R. Chaudhari U. Colhoun H.M. Efficacy and safety of the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab among high cardiovascular risk patients on maximally tolerated statin therapy: the ODYSSEY COMBO I study.Am Heart J. 2015; 169 (e13): 906-915Abstract Full Text Full Text PDF PubMed Scopus (279) Google Scholar, 7Robinson J.G. Farnier M. Krempf M. Bergeron J. Luc G. Averna M. Stroes E.S. Langslet G. Raal F.J. El Shahawy M. Koren M.J. Lepor N.E. Lorenzato C. Pordy R. Chaudhari U. Kastelein J.J.P. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events.N Engl J Med. 2015; 372: 1489-1499Crossref PubMed Scopus (1543) Google Scholar, 8Ginsberg H.N. Rader D.J. Raal F.J. Guyton J.R. Baccara-Dinet M.T. Lorenzato C. Pordy R. Stroes E. Efficacy and safety of alirocumab in patients with heterozygous familial hypercholesterolemia and LDL-C of 160 mg/dl or higher.Cardiovasc Drugs Ther. 2016; 30: 473-483Crossref PubMed Scopus (146) Google Scholar Clinical ASCVD was defined as coronary heart disease, stroke, and peripheral arterial disease, all of presumed atherosclerotic origin.2Stone N.J. Robinson J.G. Lichtenstein A.H. Bairey Merz C.N. Blum C.B. Eckel R.H. Goldberg A.C. Gordon D. Levy D. Lloyd-Jones D.M. McBride P. Schwartz J.S. Shero S.T. Smith Jr, S.C. Watson K. Wilson P.W. American College of Cardiology/American Heart Association Task Force on Practice Guidelines2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.J Am Coll Cardiol. 2014; 63: 2889-2934Crossref PubMed Scopus (3304) Google Scholar HeFH was determined based on genetic or clinical criteria as reported previously.5Kastelein J.J. Ginsberg H.N. Langslet G. Hovingh G.K. Ceska R. Dufour R. Blom D. Civeira F. Krempf M. Lorenzato C. Zhao J. Pordy R. Baccara-Dinet M.T. Gipe D.A. Geiger M.J. Farnier M. ODYSSEY FH I and FH II: 78 week results with alirocumab treatment in 735 patients with heterozygous familial hypercholesterolaemia.Eur Heart J. 2015; 36: 2996-3003PubMed Google Scholar Further details on trials included in this analysis are presented in the Supplementary Methods. For the present analysis, efficacy data were analyzed in 2 pools based on alirocumab dose regimen (Supplementary Methods). The primary efficacy end point of this analysis was the percent change in LDL-C (calculated using the Friedewald equation) from baseline to week 24 (primary end point in the parent trials), analyzed using an intention-to-treat approach that included all data, regardless of adherence to treatment. Percent changes in other lipids (apolipoprotein B [ApoB], non–high density lipoprotein cholesterol [non–HDL-C], lipoprotein(a) [Lp(a)], and triglycerides) were also assessed, as was the achievement of LDL-C < 70 mg/dl at week 24. Safety data were analyzed descriptively in alirocumab and placebo groups according to ASCVD or HeFH status. Least squares mean lipid values were calculated from a mixed-effects model with repeated measures to account for missing data, as previously described.9Roth E.M. Taskinen M.R. Ginsberg H.N. Kastelein J.J. Colhoun H.M. Robinson J.G. Merlet L. Pordy R. Baccara-Dinet M.T. Monotherapy with the PCSK9 inhibitor alirocumab versus ezetimibe in patients with hypercholesterolemia: results of a 24 week, double-blind, randomized Phase 3 trial.Int J Cardiol. 2014; 176: 55-61Abstract Full Text Full Text PDF PubMed Scopus (234) Google Scholar At week 24, 9.1% of LDL-C values were missing for the alirocumab group (209 missing values of 2,294 in total in the intent-to-treat population of the 5 trials), and 8.6% were missing for placebo (100 missing of 1,165 in total). Further analysis details are presented in the Supplementary Methods. Patients with ASCVD (n = 2,449) or without ASCVD (n = 1,050) were pooled from FH I, FH II, HIGH FH, LONG TERM, and COMBO I. Patients with HeFH with (n = 575) or without (n = 682) ASCVD were pooled from all the trials except COMBO I, where recruited patients did not have HeFH (see Supplementary Table S1). Baseline characteristics and lipid levels were similar between the alirocumab and the placebo groups (Table 1). Most of the patients with a history of ASCVD had coronary heart disease, and the proportions with coronary heart disease, ischemic stroke, or peripheral arterial disease were comparable between treatment arms in both the overall ASCVD and the HeFH with ASCVD subgroups (Table 2). All patients in these trials were receiving maximally tolerated statin therapy as per protocols, and the majority of patients were receiving high-intensity statins (Figure 1). The most common reasons for not receiving high-intensity statins were regional practice or local labeling, muscle symptoms, and/or increased creatine kinase (Figure 1).Table 1Baseline and demographic characteristics of patients based on ASCVD and HeFH status (randomized population pooled from 5 phase 3 studies)VariableWith ASCVD (n = 2449)Without ASCVD (n = 1050)Alirocumab (n = 1615)Placebo (n = 834)Alirocumab (n = 709)Placebo (n = 341)Age (years, mean ± SD)61.3 ± 9.961.3 ± 9.652.6 ± 13.052.7 ± 13.0Men1073 (66.4%)552 (66.2%)342 (48.2%)160 (46.9%)White1499 (92.8%)780 (93.5%)640 (90.3%)292 (85.6%)Body Mass Index (kg/m2, mean ± SD)30.1 ± 5.430.3 ± 5.430.0 ± 6.030.5 ± 6.2Diabetes mellitus440 (27.2%)223 (26.7%)261 (36.8%)133 (39.0%)Heterozygous familial hypercholesterolemia370 (22.9%)205 (24.6%)468 (66.0%)214 (62.8%)Hypertension1200 (74.3%)633 (75.9%)373 (52.6%)187 (54.8%)Smokers328 (20.3%)167 (20.0%)125 (17.6%)64 (18.8%)High-intensity statin910 (56.3%)492 (59.0%)417 (58.8%)190 (55.7%)Moderate-intensity statin471 (29.2%)227 (27.2%)179 (25.2%)87 (25.5%)Ezetimibe and other non-statin lipid lowering therapies589 (36.5%)318 (38.1%)293 (41.3%)143 (41.9%)Baseline lipid parameters (mg/dL)Low-density lipoprotein cholesterol (calculated) (mg/dL, mean ± SD)120.1 ± 41.3122.8 ± 44.5142.1 ± 53.1136.5 ± 44.0Apolipoprotein B (mg/dL, mean ± SD)100.8 ± 26.9102.3 ± 29.2112.3 ± 31.8108.0 ± 26.5Non-high-density lipoprotein cholesterol (mg/dL, mean ± SD)149.4 ± 45.0152.2 ± 48.9170.0 ± 56.0163.6 ± 46.5High-density lipoprotein cholesterol (mg/dL, mean ± SD)49.6 ± 12.949.4 ± 12.651.1 ± 14.150.8 ± 13.9Lipoprotein(a) (mg/dL, median) (Q1:Q3)27.0 (9.4:74.4)25.0 (8.0:72.0)21.8 (6.9:54.7)20.0 (4.8:55.0)Triglycerides (mg/dL, median) (Q1:Q3)129.2 (92.0:179.6)131.0 (94.7:179.6)123.0 (87.0:171.0)120.0 (83.6:173.2)VariableHeFH with ASCVD (n = 575)HeFH without ASCVD (n = 682)Alirocumab (n = 370)Placebo (n = 205)Alirocumab (n = 468)Placebo (n = 214)Age (years, mean ± SD)56.9 ± 10.757.4 ± 9.649.2 ± 12.748.5 ± 12.4Men227 (61.4%)123 (60.0%)224 (47.9%)105 (49.1%)White349 (94.3%)192 (93.7%)447 (95.5%)196 (91.6%)Body Mass Index (kg/m2, mean ± SD)29.2 ± 4.830.0 ± 5.228.8 ± 5.128.4 ± 4.9Diabetes mellitus46 (12.4%)37 (18.0%)40 (8.5%)18 (8.4%)Heterozygous familial hypercholesterolemia370 (100%)205 (100%)468 (100%)214 (100%)Hypertension212 (57.3%)125 (61.0%)141 (30.1%)63 (29.4%)Smokers62 (16.8%)38 (18.5%)79 (16.9%)43 (20.1%)High-intensity statin324 (87.6%)177 (86.3%)339 (72.4%)159 (74.3%)Moderate-intensity statin26 (7.0%)17 (8.3%)84 (17.9%)32 (15.0%)Ezetimibe and other non-statin lipid lowering therapies244 (65.9%)145 (70.7%)256 (54.7%)119 (55.6%)Baseline lipid parameters (mg/dL)Low-density lipoprotein cholesterol (calculated) (mg/dL, mean ± SD)148.1 ± 53.0151.0 ± 57.1155.9 ± 55.5148.3 ± 44.9Apolipoprotein B (mg/dL, mean ± SD)117.9 ± 31.8119.2 ± 34.6118.4 ± 33.2114.2 ± 26.4Non-high-density lipoprotein cholesterol (mg/dL, mean ± SD)175.1 ± 57.1178.4 ± 60.7181.0 ± 59.5172.4 ± 47.9High-density lipoprotein cholesterol (mg/dL, mean ± SD)49.3 ± 13.948.9 ± 13.552.1 ± 14.951.0 ± 15.0Lipoprotein(a) (mg/dL, median) (Q1:Q3)37.3 (12.0:89.0)31.4 (11.5:96.0)22.2 (9.0:58.0)18.0 (5.0:57.2)Triglycerides (mg/dL, median) (Q1:Q3)119.5 (86.0:158.0)119.0 (93.0:167.0)109.9 (82.0:149.0)101.0 (76.0:142.0)High-intensity statin therapy was defined as taking atorvastatin 40–80 mg, rosuvastatin 20–40 mg, or simvastatin 80 mg at randomization. Moderate-intensity statin therapy was defined as taking atorvastatin 20–<40 mg, rosuvastatin 10–<20 mg, or simvastatin 40–<80 mg at randomization.ASCVD = atherosclerotic cardiovascular disease; HeFH = heterozygous familial hypercholesterolemia; SD = standard deviation. Open table in a new tab Table 2Medical history of patients with ASCVD (randomized population pooled from 5 phase 3 studies)VariableWith ASCVD (n = 2449)HeFH with ASCVD (n = 575)Alirocumab (n = 1615)Placebo (n = 834)Alirocumab (n = 370)Placebo (n = 205)Atherosclerotic cardiovascular disease1615 (100%)834 (100%)370 (100%)205 (100%) Coronary heart disease1454 (90.0%)766 (91.8%)351 (94.9%)196 (95.6%) Acute coronary syndrome*Includes silent myocardial infarction, acute myocardial infarction, and unstable angina.980 (60.7%)528 (63.3%)234 (63.2%)122 (59.5%) Coronary revascularization procedure1006 (62.3%)522 (62.6%)249 (67.3%)140 (68.3%) Other clinically significant coronary heart disease622 (38.5%)322 (38.6%)182 (49.2%)103 (50.2%) Peripheral arterial disease97 (6.0%)56 (6.7%)24 (6.5%)9 (4.4%) Ischemic stroke199 (12.3%)86 (10.3%)34 (9.2%)10 (4.9%)ASCVD = atherosclerotic cardiovascular disease; HeFH = heterozygous familial hypercholesterolemia.* Includes silent myocardial infarction, acute myocardial infarction, and unstable angina. Open table in a new tab High-intensity statin therapy was defined as taking atorvastatin 40–80 mg, rosuvastatin 20–40 mg, or simvastatin 80 mg at randomization. Moderate-intensity statin therapy was defined as taking atorvastatin 20–<40 mg, rosuvastatin 10–<20 mg, or simvastatin 40–<80 mg at randomization. ASCVD = atherosclerotic cardiovascular disease; HeFH = heterozygous familial hypercholesterolemia; SD = standard deviation. ASCVD = atherosclerotic cardiovascular disease; HeFH = heterozygous familial hypercholesterolemia. Alirocumab resulted in significantly greater reductions from baseline in LDL-C at week 24 versus placebo in patients with ASCVD, regardless of HeFH status (Figure 2; p 0.05, Figure 2). Additional analysis of alirocumab efficacy by the intensity of statin therapy indicated that there was no significant difference in the magnitude of LDL-C reduction in those receiving moderate- versus high-intensity concomitant statin in patients with ASCVD (interaction p values >0.05, Supplementary Figure S1). LDL-C reductions were sustained with alirocumab treatment at both doses in all subgroups over the course of the studies (Figure 3, Supplementary Figure S2). Alirocumab 150 mg Q2W up to week 78 resulted in LDL-C reductions ranging from 47.6% to 53.1% versus an increase from 2.7% to 14.6% with placebo (calculated LDL-C values ranging from 59.9 to 85.0 mg/dl with alirocumab vs 123.7 to 180.7 mg/dl with placebo) in subgroups analyzed by ASCVD and/or HeFH status (Figure 3). Similar LDL-C reductions were observed with alirocumab treatment with 75/150 mg Q2W versus placebo up to weeks 52 to 78 (Supplementary Figure S2).Figure 3Change (%) in calculated LDL-C over time with alirocumab 150 mg Q2W (A) in patients with and without ASCVD and (B) in patients with HeFH with and without ASCVD (intent-to-treat population pooled from 5 phase 3 studies). LS = least squares; SE = standard error.View Large Image Figure ViewerDownload Hi-res image Download (PPT) After alirocumab treatment, 71.9% to 80.7% (vs 5.2% to 8.2% on placebo) of patients with ASCVD and 58.9% to 66.4% (vs 0.9% to 5.2%) of those without ASCVD achieved LDL-C < 70 mg/dl at week 24 (Figure 4). In the subgroup of patients with HeFH on alirocumab, 54.7% to 69.2% (vs 1.1% to 1.9% on placebo) of those with ASCVD and 57.6% to 60.2% (vs 0% to 1.2%) of those without ASCVD achieved LDL-C < 70 mg/dl at week 24 (Figure 4). The treatment effect of alirocumab versus placebo on LDL-C goal attainment was significant, regardless of alirocumab dose, ASCVD status, and HeFH status, and of similar magnitude between subgroups (Figure 4, interaction p values >0.05 for all subgroups). Baseline LDL-C levels were highest in the subgroups with no ASCVD and in the subgroups with HeFH, and particularly the subgroup with HeFH in the alirocumab 150 mg Q2W dose group (Figure 4). The proportion of patients with ASCVD achieving LDL-C < 70 mg/dl on alirocumab and placebo was comparable between high- and moderate-intensity statin subgroups, and the treatment effect of alirocumab versus placebo on LDL-C goal attainment in patients with ASCVD was significant, regardless of alirocumab dose and statin intensity, and of similar magnitude between moderate- and high-intensity (interaction p values >0.05, Supplementary Figure S3). Significant mean percent reductions from baseline to week 24 in ApoB, non–HDL-C, Lp(a), and triglycerides were observed with both doses of alirocumab versus placebo (all p 0.05 for all). In patients with ASCVD, changes in ApoB, non–HDL-C, Lp(a), and triglycerides with alirocumab versus placebo analyzed by intensity of concomitant statin therapy were all significant (except for triglycerides treated with alirocumab 75/150 mg Q2W vs placebo in the moderate-intensity statin subgroups), and the difference in alirocumab versus placebo was similar between statin intensities (interaction p values >0.05 for all, Supplementary Figure S1).Table 3Least-squares mean % change in lipid parameters from baseline to week 24 according to ASCVD and HeFH status in studies using alirocumab 75 mg Q2W (with possible dose increase to 150 mg Q2W based on week 8 LDL-C) or alirocumab 150 mg Q2W throughout (ITT population pooled from 5 phase 3 studies)LS mean ± SE % change in lipidsStudy poolsASCVDWithout ASCVDAlirocumabPlaceboAlirocumabPlaceboApolipoprotein B75/150 mg Q2W−40.5 ± 1.1*p < 0.0005 versus placebo.−0.5 ± 1.5−39.9 ± 1.3*p < 0.0005 versus placebo.3.0 ± 1.7Interaction p-value0.2766n368188289149150 mg Q2W−53.9 ± 0.8*p < 0.0005 versus placebo.0.2 ± 1.1−47.1 ± 1.4*p < 0.0005 versus placebo.2.4 ± 2.0Interaction p-value0.0840n1153607384180LS mean ± SE % change in lipidsStudy poolsHeFH with ASCVDHeFH without ASCVDAlirocumabPlaceboAlirocumabPlaceboApolipoprotein B75/150 mg Q2W−42.5 ± 1.6*p < 0.0005 versus placebo.−0.5 ± 2.0−41.1 ± 1.4*p < 0.0005 versus placebo.4.0 ± 1.9Interaction p-value0.3288n207112265129150 mg Q2W−47.0 ± 2.2*p < 0.0005 versus placebo.−2.6 ± 2.5−47.1 ± 1.9*p < 0.0005 versus placebo.0.9 ± 2.7Interaction p-value0.4091n1469118780LS mean ± SE % change in lipidsStudy poolsASCVDWithout ASCVDAlirocumabPlaceboAlirocumabPlaceboNon-high-density lipoprotein cholesterol75/150 mg Q2W−42.4 ± 1.3*p < 0.0005 versus placebo.−2.8 ± 1.8−40.8 ± 1.5*p < 0.0005 versus placebo.7.2 ± 2.1Interaction p-value0.3910n391199302151150 mg Q2W−52.7 ± 0.7*p < 0.0005 versus placebo.−0.6 ± 1.0−46.5 ± 1.3*p < 0.0005 versus placebo.3.9 ± 1.8Interaction p-value0.5028n1201626400189LS mean ± SE % change in lipidsStudy poolsHeFH with ASCVDHeFH without ASCVDAlirocumabPlaceboAlirocumabPlaceboNon-high-density lipoprotein cholesterol75/150 mg Q2W−44.9 ± 1.9*p < 0.0005 versus placebo.4.1 ± 2.5−41.1 ± 1.7*p < 0.0005 versus placebo.10.2 ± 2.2Interaction p-value0.5662n216113272131150 mg Q2W−48.6 ± 2.3*p < 0.0005 versus placebo.−1.5 ± 2.6−48.9 ± 1.9*p < 0.0005 versus placebo.4.8 ± 2.8Interaction p-value0.1561n1529219482LS mean ± SE % change in lipidsStudy poolsASCVDWithout ASCVDAlirocumabPlaceboAlirocumabPlaceboLipoprotein(a)†Adjusted mean ± SE.75/150 mg Q2W−25.9 ± 1.3*p < 0.0005 versus placebo.−8.8 ± 1.9−23.9 ± 1.5*p < 0.0005 versus placebo.−6.2 ± 2.1Interaction p-value0.8539n391199302151150 mg Q2W−29.8 ± 0.8*p < 0.0005 versus placebo.−4.4 ± 1.1−27.0 ± 1.5*p < 0.0005 versus placebo.−3.0 ± 2.1Interaction p-value0.6238n1201626400189LS mean ± SE % change in lipidsStudy poolsHeFH with ASCVDHeFH without ASCVDAlirocumabPlaceboAlirocumabPlaceboLipoprotein(a)†Adjusted mean ± SE.75/150 mg Q2W−27.2 ± 1.9*p < 0.0005 versus placebo.−8.5 ± 2.5−26.7 ± 1.7*p < 0.0005 versus placebo.−8.6 ± 2.3Interaction p-value0.8837n216113272131150 mg Q2W−22.0 ± 2.5*p < 0.0005 versus placebo.−2.7 ± 2.8−29.3 ± 2.2*p < 0.0005 versus placebo.−3.2 ± 3.0Interaction p-value0.1764n1529219483LS mean ± SE % change in lipidsStudy poolsASCVDWithout ASCVDAlirocumabPlaceboAlirocumabPlaceboTriglycerides†Adjusted mean ± SE.75/150 mg Q2W−7.7 ± 1.5*p < 0.0005 versus placebo.1.0 ± 2.1−10.2 ± 1.7*p < 0.0005 versus placebo.1.0 ± 2.1Interaction p-value0.3301n391199302151150 mg Q2W−15.8 ± 0.9*p < 0.0005 versus placebo.0.7 ± 1.3−13.9 ± 1.6*p < 0.0005 versus placebo.5.3 ± 2.4Interaction p-value0.3922n1201626400189LS mean ± SE % change in lipidsStudy poolsHeFH with ASCVDHeFH without ASCVDAlirocumabPlaceboAlirocumabPlaceboTriglycerides†Adjusted mean ± SE.75/150 mg Q2W−9.6 ± 2.1*p < 0.0005 versus placebo.5.3 ± 2.7−10.3 ± 1.8*p < 0.0005 versus placebo.3.1 ± 2.5Interaction p-value0.7173n216113272131150 mg Q2W−12.8 ± 2.9*p < 0.0005 versus placebo.1.7 ± 3.3−13.2 ± 2.5‡p = 0.006 versus placebo.−1.8 ± 3.6Interaction p-value0.6047n1529219482ASCVD = atherosclerotic cardiovascular disease; HeFH = heterozygous familial hypercholesterolemia; ITT = intent-to-treat; LDL-C = low-density lipoprotein cholesterol; LS = least squares; Q2W = every 2 weeks; SE = standard error.* p < 0.0005 versus placebo.† Adjusted mean ± SE.‡ p = 0.006 versus placebo. Open table in a new tab ASCVD = atherosclerotic cardiovascular disease; HeFH = heterozygous familial hypercholesterolemia; ITT = intent-to-treat; LDL-C = low-density lipoprotein cholesterol; LS = least squares; Q2W = every 2 weeks; SE = standard error. Overall, alirocumab and placebo showed similar safety profiles when analyzed according to ASCVD and/or HeFH status, except for a higher rate of injection-site reactions with alirocumab (Table 4).Table 4Overall safety in patients analyzed based on ASCVD and/or HeFH status (safety population)VariableWith ASCVDWithout ASCVDAlirocumab (n = 1611)Placebo (n = 834)Alirocumab (n = 707)Placebo (n = 340)Patients with any treatment-emergent adverse event*Adverse events recorded during the treatment-emergent adverse event period (i.e. from first dose up to last dose of study treatment plus 70 days).1299 (80.6%)671 (80.5%)552 (78.1%)283 (83.2%)Patients with treatment-emergent serious adverse event321 (19.9%)168 (20.1%)64 (9.1%)34 (10.0%)Patients with treatment-emergent adverse event leading to death13 (0.8%)12 (1.4%)3 (0.4%)1 (0.3%)Patients with treatment-emergent adverse event leading to discontinuation105 (6.5%)52 (6.2%)39 (5.5%)15 (4.4%)Patients with injection-site reaction105 (6.5%)36 (4.3%)62 (8.8%)26 (7.6%)VariableHeFH with ASCVDHeFH without ASCVDAlirocumab (n = 370)Placebo (n = 205)Alirocumab (n = 467)Placebo (n = 213)Patients with any treatment-emergent adverse event*Adverse events recorded during the treatment-emergent adverse event period (i.e. from first dose up to last dose of study treatment plus 70 days).305 (82.4%)171 (83.4%)369 (79.0%)176 (82.6%)Patients with treatment-emergent serious adverse event76 (20.5%)38 (18.5%)38 (8.1%)17 (8.0%)Patients with treatment-emergent adverse event leading to death5 (1.4%)2 (1.0%)2 (0.4%)0Patients with treatment-emergent adverse event leading to discontinuation15 (4.1%)8 (3.9%)18 (3.9%)7 (3.3%)Patients with injection-site reaction36 (9.7%)13 (6.3%)59 (12.6%)23 (10.8%)Data pooled from 5 Phase 3 trials: LONG TERM, HIGH FH, FH I, FH II, and COMBO I.ASCVD = atherosclerotic cardiovascular disease; HeFH = heterozygous familial hypercholesterolemia.* Adverse events recorded during the treatment-emergent adverse event period (i.e. from first dose up to last dose of study treatment plus 70 days). Open table in a new tab Data pooled from 5 Phase 3 trials: LONG TERM, HIGH FH, FH I, FH II, and COMBO I. ASCVD = atherosclerotic cardiovascular disease; HeFH = heterozygous familial hypercholesterolemia. In this analysis from 5 placebo-controlled phase 3 trials, we found that alirocumab versus placebo treatment over 52 to 78 weeks resulted in significant and substantial LDL-C lowering in patients who had LDL-C levels above goal at baseline despite maximally tolerated statin therapy (± other lipid-lowering therapies). Alirocumab significantly reduced LDL-C levels from baseline to week 24 by 46.6% to 51.3% for alirocumab 75/150 mg and 54.1% to 61.9% for alirocumab 150 mg, regardless of ASCVD and/or HeFH status. Although all patients were on maximally tolerated statin as per study protocol, ~42% of patients with ASCVD and 12.9% to 27.0% of patients with HeFH were not on high-intensity statins but were on lower doses, mainly because of muscle symptoms or increased creatine kinase levels, or because of local practice or label restrictions. LDL-C reductions were sustained for up to 78 weeks, suggesting no loss of efficacy over time. Additionally, Lp(a), ApoB, and non–HDL-C, which are considered as important lipid treatment targets along with LDL-C,1Catapano A.L. Graham I. De Backer G. Wiklund O. Chapman M.J. Drexel H. Hoes A.W. Jennings C.S. Landmesser U. Pedersen T.R. Reiner Z. Riccardi G. Taskinen M.R. Tokgozoglu L. Verschuren W.M. Vlachopoulos C. Wood D.A. Zamorano J.L. Authors/Task Force Members, Additional Contributor2016 ESC/EAS guidelines for the management of dyslipidaemias.Eur Heart J. 2016; 37: 2999-3058Crossref PubMed Scopus (2042) Google Scholar, 10Bays H.E. Jones P.H. Orringer C.E. Brown W.V. Jacobson T.A. National Lipid Association Annual Summary of Clinical Lipidology 2016.J Clin Lipidol. 2016; 10: S1-S43Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar were significantly reduced with alirocumab in patients with or without ASCVD and in patients with HeFH with or without ASCVD. Alirocumab was generally well tolerated in these patient populations, with overall treatment-emergent adverse event frequencies similar to placebo except for a higher rate of injection-site reactions (mostly mild). The reduction in LDL-C in alirocumab-treated patients analyzed by ASCVD and/or HeFH status was similar to the 49.6% to 60.4% reduction observed in the analysis of the overall population pooled from 8 ODYSSEY phase 3 trials.11Farnier M. Gaudet D. Valcheva V. Minini P. Miller K. Cariou B. Efficacy of alirocumab in high cardiovascular risk populations with or without heterozygous familial hypercholesterolemia: pooled analysis of eight ODYSSEY Phase 3 clinical program trials.Int J Cardiol. 2016; 223: 750-757Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar Most patients (ASCVD and/or HeFH) who received alirocumab achieved their LDL-C treatment goal. Compared with the overall ASCVD group, a lower proportion of patients without ASCVD, or with HeFH (regardless of ASCVD status), achieved LDL-C < 70 mg/dl, which may be explained by the higher baseline LDL-C levels in the subgroup without ASCVD and in the subgroups with HeFH. Similarly, a lower achievement of LDL-C < 70 mg/dl was observed in the HeFH subgroups with the alirocumab 150 mg Q2W dose compared with the 75/150 mg Q2W dose, which again may be explained by higher baseline LDL-C levels in those who received alirocumab 150 mg Q2W (a large proportion of whom were from the HIGH FH study in patients with HeFH with high baseline LDL-C [>160 mg/dl]). Higher baseline LDL-C levels were found to be the main predictive factor for requiring alirocumab dose increase (due to not achieving the LDL-C goal) in an analysis of 6 phase 3 trials.12Kastelein J.J. Kereiakes D.J. Cannon C.P. Bays H.E. Minini P. Lee L.V. Maroni J. Farnier M. Effect of alirocumab dose increase on LDL lowering and lipid goal attainment in patients with dyslipidemia.Coron Artery Dis. 2017; 28: 190-197Crossref PubMed Scopus (19) Google Scholar Our study has all the limitations of retrospective studies of prospectively collected data from different clinical trials.13Brookes S.T. Whitley E. Peters T.J. Mulheran P.A. Egger M. Davey Smith G. Subgroup analyses in randomised controlled trials: quantifying the risks of false-positives and false-negatives.Health Technol Assess. 2001; 5: 1-56Crossref PubMed Scopus (368) Google Scholar We recognize that this is a post hoc, pooled analysis that was conducted after randomization. The generalization of the safety findings is limited by the exclusion criteria, the sample size, and the duration of studies; however, they are consistent with overall safety data reported from across 14 alirocumab phase 2 and 3 clinical trials.14Jones P.H. Bays H.E. Chaudhari U. Pordy R. Lorenzato C. Miller K. Robinson J.G. Safety of alirocumab (a PCSK9 monoclonal antibody) from 14 randomized trials.Am J Cardiol. 2016; 118: 1805-1811Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar Patients with a history of ASCVD, and especially those with ASCVD and HeFH, are at an increased risk of further events.15Nanchen D. Gencer B. Muller O. Auer R. Aghlmandi S. Heg D. Klingenberg R. Raber L. Carballo D. Carballo S. Matter C.M. Luscher T.F. Windecker S. Mach F. Rodondi N. Prognosis of patients with familial hypercholesterolemia after acute coronary syndromes.Circulation. 2016; 134: 698-709Crossref PubMed Scopus (91) Google Scholar These data demonstrate that in these high-risk patient populations, further LDL-C reduction is achievable with alirocumab. Trials comparing high- versus low-intensity statins, as well as the Improved Reduction of Outcomes: Vytorin Efficacy International Trial (which compared adding ezetimibe to simvastatin with adding placebo), have indicated that incremental reductions in LDL-C can produce further reduction in the risk of major cardiovascular events.16Cannon C.P. Blazing M.A. Giugliano R.P. McCagg A. White J.A. Theroux P. Darius H. Lewis B.S. Ophuis T.O. Jukema J.W. De Ferrari G.M. Ruzyllo W. De Lucca P. Im K. Bohula E.A. Reist C. Wiviott S.D. Tershakovec A.M. Musliner T.A. Braunwald E. Califf R.M. IMPROVE-IT InvestigatorsEzetimibe added to statin therapy after acute coronary syndromes.N Engl J Med. 2015; 372: 2387-2397Crossref PubMed Scopus (2778) Google Scholar, 17Baigent C. Blackwell L. Emberson J. Holland L.E. Reith C. Bhala N. Peto R. Barnes E.H. Keech A. Simes J. Collins R. Cholesterol Treatment Trialists CollaborationEfficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials.Lancet. 2010; 376: 1670-1681Abstract Full Text Full Text PDF PubMed Scopus (4534) Google Scholar Data from the Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk cardiovascular outcomes trial showed a significant reduction in both myocardial infarction and stroke versus placebo from adding the PCSK9 inhibitor evolocumab to statin therapy.18Sabatine M.S. Giugliano R.P. Keech A.C. Honarpour N. Wiviott S.D. Murphy S.A. Kuder J.F. Wang H. Liu T. Wasserman S.M. Sever P.S. Pedersen T.R. Evolocumab and clinical outcomes in patients with cardiovascular disease.N Engl J Med. 2017; 376: 1713-1722Crossref PubMed Scopus (3166) Google Scholar The rate of major adverse cardiovascular events was 48% lower among alirocumab-treated compared with placebo-treated patients in a post hoc safety analysis of LONG TERM, a 78-week phase 3 study.7Robinson J.G. Farnier M. Krempf M. Bergeron J. Luc G. Averna M. Stroes E.S. Langslet G. Raal F.J. El Shahawy M. Koren M.J. Lepor N.E. Lorenzato C. Pordy R. Chaudhari U. Kastelein J.J.P. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events.N Engl J Med. 2015; 372: 1489-1499Crossref PubMed Scopus (1543) Google Scholar A post hoc analysis of data from 10 alirocumab phase 3 trials suggested that the relation between lower LDL-C levels and reduced cardiovascular risk extended to levels below 50 mg/dl19Ray K.K. Ginsberg H.N. Davidson M.H. Pordy R. Bessac L. Minini P. Eckel R.H. Cannon C.P. Reductions in atherogenic lipids and major cardiovascular events: a pooled analysis of 10 ODYSSEY trials comparing alirocumab with control.Circulation. 2016; 134: 1931-1943Crossref PubMed Scopus (86) Google Scholar; however, this finding needs to be confirmed in the alirocumab cardiovascular outcomes trial (ODYSSEY OUTCOMES, ~18,000 patients with ASCVD with or without HeFH).20Schwartz G.G. Bessac L. Berdan L.G. Bhatt D.L. Bittner V. Diaz R. Goodman S.G. Hanotin C. Harrington R.A. Jukema J.W. Mahaffey K.W. Moryusef A. Pordy R. Roe M.T. Rorick T. Sasiela W.J. Shirodaria C. Szarek M. Tamby J.F. Tricoci P. White H. Zeiher A. Steg P.G. Effect of alirocumab, a monoclonal antibody to PCSK9, on long-term cardiovascular outcomes following acute coronary syndromes: rationale and design of the ODYSSEY outcomes trial.Am Heart J. 2014; 168: 682-689Abstract Full Text Full Text PDF PubMed Scopus (346) Google Scholar The authors thank the patients, their families, and all investigators involved in this study; Robert Weiss, MD, FACP, FACP, FAHA, Dirk Blom, FCP(SA), PhD, and Jean Bergeron, MD, MSc, FRCPC, FAHA, for their contributions to the data interpretation and the content of the manuscript; the following people from the study sponsors, who provided editorial comments on the manuscript: Jay Edelberg, MD, PhD (Sanofi), Michael Howard, MBA (Sanofi), L. Veronica Lee, MD (Sanofi), Robert Pordy, MD (Regeneron Pharmaceuticals, Inc.), Eva-Lynne Greene, MS (Regeneron Pharmaceuticals, Inc.), and Carol Hudson, MS (Regeneron Pharmaceuticals, Inc.); and Aparna Shetty, PhD, of Prime (Knutsford, United Kingdom), supported by Sanofi and Regeneron Pharmaceuticals, Inc., according to Good Publication Practice guidelines (http://annals.org/aim/fullarticle/2424869/good-publication-practice-communicating-company-sponsored-medical-research-gpp3), for providing medical writing support, under the direction of the authors. Dr. McCullough reports no disclosures. Dr. Ballantyne has received research grant support from Abbott Diagnostic, Amarin, Amgen, Eli Lilly, Esperion, Ionis/Akcea, Novartis, Pfizer, Regeneron Pharmaceuticals, Inc., Roche Diagnostic, Sanofi-Synthelabo, Takeda, National Institute of Health, the American Heart Association, and the American Diabetes Association; and consultant and advisory board fees from Abbott Diagnostics, Amarin, Amgen, AstraZeneca, Eli Lilly, Esperion, Genzyme, Ionis, Matinas BioPharma Inc., Merck, Novartis, Pfizer, Regeneron Pharmaceuticals, Inc., Roche Diagnostics, and Sanofi-Synthelabo. Dr. Sanganalmath reports that he is an employee and stockholder of Regeneron Pharmaceuticals, Inc. Jonas Mandel reports that he is a contractor for Sanofi. Dr. Koren reports that he is an employee and stockholder of Sanofi. Dr. Langslet has received advisory board and lecture fees from Amgen, Sanofi, Boehringer Ingelheim, and Janssen Pharmaceuticals. His institution received compensation from the study sponsor (Sanofi) for the conduct of the study. Dr. Baum has received research funding from Amgen, Sanofi, Ionis/Akcea, Aegerion, Esperion, Madrigal, Gemphire, and AstraZeneca; consultant and advisory board fees for Amgen, Regeneron Pharmaceuticals, Inc./Sanofi, AstraZeneca, and Aegerion; and honoraria for lectures for Amgen, Merck, and AstraZeneca. Dr. Shah has received research funding from Regeneron Pharmaceuticals, Inc. Dr. Davidson has received consultant and advisory board fees and honoraria, and has participated in speaker's bureaus for Sanofi, Regeneron Pharmaceuticals, Inc., and Amgen. The sponsors were involved in the study design, collection, analysis, and interpretation of data, as well as data checking of information provided in the manuscript. The authors were responsible for all content and editorial decisions and received no honoraria related to the development of this publication. The following is the supplementary data to this article: Download .docx (.51 MB) Help with docx files Appendix S1Supplementary Methods, Supplementary Table S1 and Supplementary Figures S1 to S3.

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