Long‐Term Efficacy, Safety, and Tolerability of Alirocumab in 8242 Patients Eligible for 3 to 5 Years of Placebo‐Controlled Observation in the ODYSSEY OUTCOMES Trial

Lipid‐lowering therapy is ordinarily a long‐term intervention to reduce cardiovascular risk. Yet, evaluation of long‐term efficacy and safety of lipid‐lowering therapies is often limited by the duration of randomized clinical trials. The ODYSSEY OUTCOMES trial compared alirocumab, a monoclonal antibody to PCSK9 (proprotein convertase subtilisin/kexin type 9), with placebo in 18 924 patients with a recent acute coronary syndrome followed up for up to 5 years. Over a median follow‐up of 2.8 years, alirocumab lowered low‐density lipoprotein cholesterol from a median 2.3 to 1.0 mmol/L at 4 months, reduced major adverse cardiovascular events (MACEs), ¹ was associated with fewer deaths, ² and had no excess of adverse events (AEs) except for mild‐to‐moderate local injection‐site reactions. ¹ However, the efficacy and safety of alirocumab among patients eligible for longer follow‐up have not been fully explored. The current post hoc analyses describe the efficacy, safety, and tolerability of alirocumab versus placebo in a prespecified subgroup ² of patients eligible for ≥3 years of follow‐up (ie, randomized ≥3 years before the common study end date).

At each participating site, the study was approved by the responsible institutional review committee, and subjects gave informed consent. Hazard ratios (HRs) were calculated using Cox regression models, and P values were obtained using log‐rank tests. Analyses were stratified by geographic region. Two assessments were performed for both the MACE and cardiovascular death end points to ensure that the proportional hazards model assumptions over time were met: log{−log[S(t)]} versus log[time] (identifying parallel curves) and interaction treatment×time (P _interaction=0.19 for MACE, and P _interaction=0.43 for cardiovascular death). Data that support the findings of this study are available from the corresponding author on reasonable request.

Of 8242 patients (43.5%) eligible for 3 to 5 years' follow‐up, 8228 received ≥1 dose of study medication, comprising 24 610 patient‐years of observation, with a median follow‐up of 3.3 years; 6651 patients were eligible for 3 to 4 years’ follow‐up, and 1574 patients were eligible for 4 to 5 years' follow‐up. As previously reported in a subgroup (n=3551) with all measurements through 3 years, there was a consistent and sustained low‐density lipoprotein cholesterol reduction (53% and 62% relative versus placebo at months 1 and 36, respectively). ³ In prior prespecified analysis, alirocumab reduced death (4‐year Kaplan‐Meier estimate, 5.4% versus 7.0%; P=0.01) compared with placebo. ³ Here, we demonstrate that this was driven by a reduction in cardiovascular death (post hoc 4‐year Kaplan‐Meier estimate, 3.9% versus 5.0%; HR, 0.81 [95% CI, 0.65–1.01]; P=0.06) (Figure [A]). Alirocumab also reduced MACEs (coronary heart disease death, nonfatal myocardial infarction, fatal/nonfatal ischemic stroke, unstable angina requiring hospitalization: 12.0% versus 14.2%; HR, 0.83 [95% CI, 0.74 to 0.94]; P=0.003) (Figure [B]).

Figure 1. Clinical efficacy, safety, and tolerability in patients (n=8242 for efficacy; and n=8228 for safety) eligible for a minimum of 3 and up to 5 years of follow‐up in ODYSSEY OUTCOMES. Data are shown for cardiovascular death (A), major adverse cardiovascular events (B), adverse events (AEs)/safety (C), and local injection‐site reactions (D).

P values and NNTs for post hoc analyses are considered nominal. ALT indicates alanine transaminase; AST, aspartate transaminase; CHD, coronary heart disease; HR, hazard ratio; MI, myocardial infarction; NNT, number needed to treat; UA, unstable angina; and ULN, upper limit of normal.

In a safety analysis, 3217 (78.3%) patients in the alirocumab group versus 3303 (80.2%) patients in the placebo group had at least 1 AE, of whom 27.5% versus 29.4% had a serious AE, respectively (Figure [C]). Incident diabetes, worsening or complications of diabetes, neurocognitive events, elevation of liver transaminases to >3, elevation of bilirubin to >2, and elevation of creatine phosphokinase to >10 times the upper limit of normal, and permanent discontinuation of study drug attributable to AEs occurred with similar frequency with alirocumab versus placebo. Although local injection‐site reactions occurred more frequently with alirocumab, the cumulative incidence for time to first local injection‐site reaction was <5% over ~4 years, with most occurring within the first 6 months (Figure [D]).

Several limitations are acknowledged: (1) Patients with prior hemorrhagic stroke were excluded. (2) No formal neurocognitive testing was performed. However, a dedicated 96‐week, placebo‐controlled neurocognitive study (n=2176) showed no effect of alirocumab. ⁴ (3) The longest follow‐up in the trial was 5 years, and mean age at randomization was 59 years ¹ ; we cannot exclude the possibility that safety issues would emerge over a longer period or in an older population. However, among 5084 patients aged ≥65 years in the overall trial population, no differences in total or specific AEs were evident between treatment groups; furthermore, we have previously shown that alirocumab improved clinical outcomes in patients aged ≥65 years. ¹

Our findings represent the longest randomized, placebo‐controlled comparison of PCSK9 inhibition to date. In the FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) trial (n=27 564) comparing evolocumab with placebo, the median duration of randomized treatment was 2.2 years, during which time no difference in cardiovascular or total mortality was observed. At the conclusion of randomized treatment, 6635 (24%) participants from both treatment arms continued in an open‐label extension and received evolocumab for a total observation time up to 8 years. Extended treatment with evolocumab in the group initially randomized to evolocumab was safe, well tolerated, and associated with fewer cardiovascular events and cardiovascular deaths compared with delayed treatment with evolocumab in those initially randomized to placebo who survived the parent study. ⁵

In conclusion, among 8242 patients treated with maximum‐tolerated statin in the ODYSSEY OUTCOMES trial eligible for 3 to 5 years of placebo‐controlled follow‐up, comprising 24 610 patient‐years of observation, alirocumab reduced the risk of MACEs and death after acute coronary syndrome without differences in specific safety or overall AEs. These benefits were observed in the context of substantial and sustained lowering of low‐density lipoprotein cholesterol with alirocumab versus placebo, consistent with that achieved with alirocumab in the overall trial population, and comparable to that observed with statins versus placebo in Cholesterol Treatment Trialists’ meta‐analyses, where progressively greater benefits were observed with longer duration of low‐density lipoprotein cholesterol lowering. The tolerability of alirocumab was indistinguishable from placebo, except for a small excess of local injection‐site reactions. Thus, alirocumab appears to be a safe, well‐tolerated, and effective lipid‐modifying and outcome‐improving treatment when used for up to 5 years.

Sources of Funding

This work was supported by Sanofi and Regeneron Pharmaceuticals.

Disclosures

Dr Goodman reports research grant support (eg, steering committee or data and safety monitoring committee) and/or speaker/consulting honoraria (eg, advisory boards) from: Amgen, Anthos Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, CSL Behring, Daiichi‐Sankyo/American Regent, Eli Lilly, Esperion, Ferring Pharmaceuticals, HLS Therapeutics, JAMP Pharma, Merck, Novartis, Novo Nordisk A/C, Pendopharm/Pharmascience, Pfizer, Regeneron, Sanofi, Servier, Valeo Pharma; and salary support/honoraria from the Heart and Stroke Foundation of Ontario/University of Toronto (Polo) Chair, Canadian Heart Research Centre and MD Primer, Canadian VIGOUR Centre, Cleveland Clinic Coordinating Center for Clinical Research, Duke Clinical Research Institute, New York University Clinical Coordinating Center, PERFUSE Research Institute, TIMI (Thrombolysis in Myocardial Infarction) Study Group (Brigham Health). Dr Steg reports grants, personal fees, and nonfinancial support from Sanofi; grants and personal fees from Amarin, Servier, and Bayer; personal fees from Amgen, AstraZeneca, BMS, Boehringer Ingelheim, Idorsia, Pfizer, and Novartis. Dr Steg has a patent use of alirocumab to reduce risk after acute coronary syndrome (royalties to Sanofi) pending. Y. Poulouin is an IT&M Stats employee, and IT&M Stats reports consultancy fees from Sanofi. Dr Bhatt discloses the following relationships: advisory board: AngioWave, Bayer, Boehringer Ingelheim, Cardax, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, High Enroll, Janssen, Level Ex, McKinsey, Medscape Cardiology, Merck, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, Regado Biosciences, Stasys; board of directors: AngioWave (stock options), Boston VA Research Institute, Bristol Myers Squibb (stock), DRS.LINQ (stock options), High Enroll (stock), Society of Cardiovascular Patient Care, TobeSoft; chair: Inaugural Chair, American Heart Association Quality Oversight Committee; consultant: Broadview Ventures; data monitoring committees: Acesion Pharma, Assistance Publique–Hôpitaux de Paris, Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO (Portico Transcatheter Heart Valve and Delivery Systems) trial, funded by St. Jude Medical, now Abbott), Boston Scientific (Chair, PEITHO [Pulmonary Embolism Thrombolysis] trial), Cleveland Clinic (including for the ExCEED [CENTERA THV System in Intermediate Risk Patients Who Have Symptomatic, Severe, Calcific, Aortic Stenosis] trial, funded by Edwards), Contego Medical (Chair, PERFORMANCE 2), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE [Edoxaban Compared to Standard Care After Heart Valve Replacement Using a Catheter in Patients With Atrial Fibrillation] trial, funded by Daiichi Sankyo; for the ABILITY‐DM [Randomized Comparison of Abluminus DES+Sirolimus‐Eluting Stents Versus Everolimus‐Eluting Stents in Coronary Artery Disease Patients With Diabetes Mellitus Global] trial, funded by Concept Medical), Novartis, Population Health Research Institute; Rutgers University (for the National Institutes of Health–funded MINT [Myocardial Ischemia and Transfusion] Trial); honoraria: American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Chair, ACC Accreditation Oversight Committee), Arnold and Porter law firm (work related to Sanofi/Bristol‐Myers Squibb clopidogrel litigation), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE‐DUAL PCI [Evaluation of Dual Therapy with Dabigatran vs. Triple Therapy with Warfarin in Patients with Atrial Fibrillation that Undergo a Percutaneous Coronary Intervention with Stenting] clinical trial steering committee funded by Boehringer Ingelheim; AEGIS‐II executive committee funded by CSL Behring), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), Cowen and Company, Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE [A Trial Comparing Cardiovascular Safety of Degarelix Versus Leuprolide in Patients with Advanced Prostate Cancer and Cardiovascular Disease] trial, funded by Ferring Pharmaceuticals), HMP Global (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), K2P (Co‐Chair, interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (continuing medical education [CME] steering committees), MJH Life Sciences, Oakstone CME (Course Director, Comprehensive Review of Interventional Cardiology), Piper Sandler, Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and USA national coleader, funded by Bayer), Slack Publications (Chief Medical Editor, Cardiology Today's Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), WebMD (CME steering committees), Wiley (steering committee); other: Clinical Cardiology (Deputy Editor), NCDR‐ACTION (National Cardiovascular Data Registry‐Acute Coronary Treatment and Intervention Outcomes Network) Registry Steering Committee (Chair), VA CART (Veterans Affairs Clinical Assessment, Reporting, and Tracking) Research and Publications Committee (Chair); patent: sotagliflozin (named on a patent for sotagliflozin assigned to Brigham and Women's Hospital who assigned to Lexicon; neither I nor Brigham and Women's Hospital receive any income from this patent); research funding: Abbott, Acesion Pharma, Afimmune, Aker Biomarine, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Boston Scientific, Bristol‐Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, CinCor, CSL Behring, Eisai, Ethicon, Faraday Pharmaceuticals, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Javelin, Lexicon, Lilly, Medtronic, Merck, Moderna, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Owkin, Pfizer, PhaseBio, PLx Pharma, Recardio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, Youngene, 89Bio; royalties: Elsevier (Editor, Braunwald's Heart Disease); site coinvestigator: Abbott, Biotronik, Boston Scientific, CSI, Endotronix, St. Jude Medical (now Abbott), Philips, SpectraWAVE, Svelte, Vascular Solutions; trustee: American College of Cardiology; unfunded research: FlowCo, Takeda. Dr Bittner reports grant support from Sanofi, Regeneron Pharmaceuticals, Amgen, AstraZeneca, DalCor, Esperion, and Novartis; consulting fees from Pfizer; honoraria from Medscape; and fees for participating on data safety monitoring boards for the National Institutes of Health and Verve Therapeutics. Dr Diaz reports research grants from Sanofi, DalCor Pharmaceuticals, Population Health Research Institute, Duke Clinical Research Institute, the TIMI group, Amgen, Cirius, Montreal Health Innovations Coordinating Center, and Lepetit; and personal fees, as a member of the Executive Steering Committee, from Amgen and Cirius. G. Garon and Dr Stipek are employees of Sanofi and may hold shares in the company. Dr Harrington reports research grants from the Patient‐Centered Outcomes Research Institute, National Institutes of Health, CSL, and Janssen; consulting for Atropos Health, Bitterroot Bio, Bridge Bio, Bristol Myers Squibb, Foresight, Element Science; and serving on the boards of directors for the American Heart Association (unpaid) and Cytokinetics. Dr Jukema reports research grants from the Netherlands Heart Foundation, the Interuniversity Cardiology Institute of the Netherlands, and the European Commission Seventh Framework Programme; and research support from Amgen, Astellas, AstraZeneca, Daiichi‐ Sankyo, Lilly, Merck‐Schering‐Plough, Novartis, Pfizer, Roche, and Sanofi. Dr Manvelian is an employee of Regeneron Pharmaceuticals, Inc. Dr Szarek reports serving as a consultant or on advisory boards (or both) for CiVi, Resverlogix, Baxter, Esperion, Sanofi, and Regeneron Pharmaceuticals, Inc. Dr White reports grant support paid to the institution for serving on a Steering Committee for the ODYSSEY OUTCOMES trial (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) from Sanofi‐Aventis and Regeneron Pharmaceuticals, for the STRENGTH trial (Outcomes Study to Assess Statin Residual Risk Reduction With EpaNova in High CV Risk Patients With Hypertriglyceridemia) from Omthera Pharmaceuticals for the HEART‐FID study (Randomized Placebo‐Controlled Trial of FCM as Treatment for Heart Failure With Iron Deficiency) from American Regent, and for the ISCHEMIA Trial (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches) and the MINT Trial (Myocardial Ischemia and Transfusion) from the National Institutes of Health. He also received grants to the institution and personal fees as Steering Committee member for the dal‐GenE study (Effect of Dalcetrapib vs. Placebo on CV Risk in a Genetically Defined Population With a Recent ACS) from DalCor Pharma UK Inc, for the AEGIS‐II study (The Safety and Tolerability of CSL112, a Reconstituted, Infusible, Plasma‐Derived Human ApoA‐I, After Acute Myocardial Infarction: The ApoA‐I Event Reducing in Ischemic Syndromes I) from CSL Behring, for the SCORED trial (Effect of Sotagliflozin on Cardiovascular and Renal Events in Patients With Type 2 Diabetes and Moderate Renal Impairment Who Are at Cardiovascular Risk) and the SOLOIST‐WHF trial (Effect of Sotagliflozin on Cardiovascular Events in Patients With Type2 Diabetes Post Worsening Heart Failure) from Sanofi‐Aventis Australia Pty Ltd, and for the CLEAR Outcomes Study (Evaluation of Major Cardiovascular Events in Patients With, or at High Risk for, Cardiovascular Disease Who Are Statin Intolerant Treated With Bempedoic Acid [ETC‐1002] or Placebo) from Esperion Therapeutics Inc. H.D.W. was on the Advisory Boards for CSL Behring and Genentech, Inc. (an affiliate of F. Hoffmann‐La Roche Ltd, “Roche”; Lytics Post‐PCI Advisory Board at European Society of Cardiology. Dr Schwartz reports research grants to the University of Colorado from AstraZeneca, Resverlogix, Sanofi, Silence Therapeutics, and The Medicines Company; and is coinventor of pending US patent 62/806313 (“Methods for Reducing Cardiovascular Risk”) assigned in full to the University of Colorado.

Supporting information

Data S1