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Effect of Evolocumab on Progression of Coronary Disease in Statin-Treated Patients: The GLAGOV Randomized Clinical Trial.
JAMA. 2016 12 13; 316(22):2373-2384.JAMA

Abstract

Importance

Reducing levels of low-density lipoprotein cholesterol (LDL-C) with intensive statin therapy reduces progression of coronary atherosclerosis in proportion to achieved LDL-C levels. Proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors produce incremental LDL-C lowering in statin-treated patients; however, the effects of these drugs on coronary atherosclerosis have not been evaluated.

Objective

To determine the effects of PCSK9 inhibition with evolocumab on progression of coronary atherosclerosis in statin-treated patients.

Design, Setting, and Participants

The GLAGOV multicenter, double-blind, placebo-controlled, randomized clinical trial (enrollment May 3, 2013, to January 12, 2015) conducted at 197 academic and community hospitals in North America, Europe, South America, Asia, Australia, and South Africa and enrolling 968 patients presenting for coronary angiography.

Interventions

Participants with angiographic coronary disease were randomized to receive monthly evolocumab (420 mg) (n = 484) or placebo (n = 484) via subcutaneous injection for 76 weeks, in addition to statins.

Main Outcomes and Measures

The primary efficacy measure was the nominal change in percent atheroma volume (PAV) from baseline to week 78, measured by serial intravascular ultrasonography (IVUS) imaging. Secondary efficacy measures were nominal change in normalized total atheroma volume (TAV) and percentage of patients demonstrating plaque regression. Safety and tolerability were also evaluated.

Results

Among the 968 treated patients (mean age, 59.8 years [SD, 9.2]; 269 [27.8%] women; mean LDL-C level, 92.5 mg/dL [SD, 27.2]), 846 had evaluable imaging at follow-up. Compared with placebo, the evolocumab group achieved lower mean, time-weighted LDL-C levels (93.0 vs 36.6 mg/dL; difference, -56.5 mg/dL [95% CI, -59.7 to -53.4]; P < .001). The primary efficacy parameter, PAV, increased 0.05% with placebo and decreased 0.95% with evolocumab (difference, -1.0% [95% CI, -1.8% to -0.64%]; P < .001). The secondary efficacy parameter, normalized TAV, decreased 0.9 mm3 with placebo and 5.8 mm3 with evolocumab (difference, -4.9 mm3 [95% CI, -7.3 to -2.5]; P < .001). Evolocumab induced plaque regression in a greater percentage of patients than placebo (64.3% vs 47.3%; difference, 17.0% [95% CI, 10.4% to 23.6%]; P < .001 for PAV and 61.5% vs 48.9%; difference, 12.5% [95% CI, 5.9% to 19.2%]; P < .001 for TAV).

Conclusions and Relevance

Among patients with angiographic coronary disease treated with statins, addition of evolocumab, compared with placebo, resulted in a greater decrease in PAV after 76 weeks of treatment. Further studies are needed to assess the effects of PCSK9 inhibition on clinical outcomes.

Trial Registration

clinicaltrials.gov Identifier: NCT01813422.

Authors+Show Affiliations

South Australian Health and Medical Research Institute, University of Adelaide, Adelaide, Australia2Department of Cardiovascular Medicine, Cleveland Clinic Coordinating Center for Clinical Research, Cleveland, Ohio.Department of Cardiovascular Medicine, Cleveland Clinic Coordinating Center for Clinical Research, Cleveland, Ohio.Libin Cardiovascular Institute, University of Calgary, Calgary, Alberta, Canada.The Methodist DeBakey Heart and Vascular Center, Section of Cardiovascular Research, Baylor College of Medicine, Houston, Texas.Department of Cardiovascular Medicine, Cleveland Clinic Coordinating Center for Clinical Research, Cleveland, Ohio.Academic Medical Center, Department of Vascular Medicine, University of Amsterdam, Amsterdam, the Netherlands.Deutsches Herzzentrum München, Technische Universität München, Munich, Germany7DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany8Department of Internal Medicine, University of Ulm Medical Center, Ulm, Germany.Amgen Inc, Thousand Oaks, California.Amgen Inc, Thousand Oaks, California.Amgen Inc, Thousand Oaks, California.Amgen Inc, Thousand Oaks, California.Amgen Inc, Thousand Oaks, California.Department of Cardiology, University of Szeged, Hungary.Department of Interventional Cardiology, Cardiology Institute, Jagiellonian University, College of Medicine and the John Paul II Hospital, Krakow, Poland.Department of Cardiology, Canisius Wilhelmina Hospital, Nijmegen, the Netherlands.Department of Cardiology, Noordwest Ziekenhuisgroep, Alkmaar, the Netherlands.Department of Cardiovascular Medicine, Cleveland Clinic Coordinating Center for Clinical Research, Cleveland, Ohio.Department of Cardiovascular Medicine, Cleveland Clinic Coordinating Center for Clinical Research, Cleveland, Ohio.Department of Cardiovascular Medicine, Cleveland Clinic Coordinating Center for Clinical Research, Cleveland, Ohio.

Pub Type(s)

Journal Article
Multicenter Study
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

27846344

Citation

Nicholls, Stephen J., et al. "Effect of Evolocumab On Progression of Coronary Disease in Statin-Treated Patients: the GLAGOV Randomized Clinical Trial." JAMA, vol. 316, no. 22, 2016, pp. 2373-2384.
Nicholls SJ, Puri R, Anderson T, et al. Effect of Evolocumab on Progression of Coronary Disease in Statin-Treated Patients: The GLAGOV Randomized Clinical Trial. JAMA. 2016;316(22):2373-2384.
Nicholls, S. J., Puri, R., Anderson, T., Ballantyne, C. M., Cho, L., Kastelein, J. J., Koenig, W., Somaratne, R., Kassahun, H., Yang, J., Wasserman, S. M., Scott, R., Ungi, I., Podolec, J., Ophuis, A. O., Cornel, J. H., Borgman, M., Brennan, D. M., & Nissen, S. E. (2016). Effect of Evolocumab on Progression of Coronary Disease in Statin-Treated Patients: The GLAGOV Randomized Clinical Trial. JAMA, 316(22), 2373-2384. https://doi.org/10.1001/jama.2016.16951
Nicholls SJ, et al. Effect of Evolocumab On Progression of Coronary Disease in Statin-Treated Patients: the GLAGOV Randomized Clinical Trial. JAMA. 2016 12 13;316(22):2373-2384. PubMed PMID: 27846344.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Effect of Evolocumab on Progression of Coronary Disease in Statin-Treated Patients: The GLAGOV Randomized Clinical Trial. AU - Nicholls,Stephen J, AU - Puri,Rishi, AU - Anderson,Todd, AU - Ballantyne,Christie M, AU - Cho,Leslie, AU - Kastelein,John J P, AU - Koenig,Wolfgang, AU - Somaratne,Ransi, AU - Kassahun,Helina, AU - Yang,Jingyuan, AU - Wasserman,Scott M, AU - Scott,Robert, AU - Ungi,Imre, AU - Podolec,Jakub, AU - Ophuis,Antonius Oude, AU - Cornel,Jan H, AU - Borgman,Marilyn, AU - Brennan,Danielle M, AU - Nissen,Steven E, PY - 2016/11/16/pubmed PY - 2017/2/9/medline PY - 2016/11/16/entrez SP - 2373 EP - 2384 JF - JAMA JO - JAMA VL - 316 IS - 22 N2 - Importance: Reducing levels of low-density lipoprotein cholesterol (LDL-C) with intensive statin therapy reduces progression of coronary atherosclerosis in proportion to achieved LDL-C levels. Proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors produce incremental LDL-C lowering in statin-treated patients; however, the effects of these drugs on coronary atherosclerosis have not been evaluated. Objective: To determine the effects of PCSK9 inhibition with evolocumab on progression of coronary atherosclerosis in statin-treated patients. Design, Setting, and Participants: The GLAGOV multicenter, double-blind, placebo-controlled, randomized clinical trial (enrollment May 3, 2013, to January 12, 2015) conducted at 197 academic and community hospitals in North America, Europe, South America, Asia, Australia, and South Africa and enrolling 968 patients presenting for coronary angiography. Interventions: Participants with angiographic coronary disease were randomized to receive monthly evolocumab (420 mg) (n = 484) or placebo (n = 484) via subcutaneous injection for 76 weeks, in addition to statins. Main Outcomes and Measures: The primary efficacy measure was the nominal change in percent atheroma volume (PAV) from baseline to week 78, measured by serial intravascular ultrasonography (IVUS) imaging. Secondary efficacy measures were nominal change in normalized total atheroma volume (TAV) and percentage of patients demonstrating plaque regression. Safety and tolerability were also evaluated. Results: Among the 968 treated patients (mean age, 59.8 years [SD, 9.2]; 269 [27.8%] women; mean LDL-C level, 92.5 mg/dL [SD, 27.2]), 846 had evaluable imaging at follow-up. Compared with placebo, the evolocumab group achieved lower mean, time-weighted LDL-C levels (93.0 vs 36.6 mg/dL; difference, -56.5 mg/dL [95% CI, -59.7 to -53.4]; P < .001). The primary efficacy parameter, PAV, increased 0.05% with placebo and decreased 0.95% with evolocumab (difference, -1.0% [95% CI, -1.8% to -0.64%]; P < .001). The secondary efficacy parameter, normalized TAV, decreased 0.9 mm3 with placebo and 5.8 mm3 with evolocumab (difference, -4.9 mm3 [95% CI, -7.3 to -2.5]; P < .001). Evolocumab induced plaque regression in a greater percentage of patients than placebo (64.3% vs 47.3%; difference, 17.0% [95% CI, 10.4% to 23.6%]; P < .001 for PAV and 61.5% vs 48.9%; difference, 12.5% [95% CI, 5.9% to 19.2%]; P < .001 for TAV). Conclusions and Relevance: Among patients with angiographic coronary disease treated with statins, addition of evolocumab, compared with placebo, resulted in a greater decrease in PAV after 76 weeks of treatment. Further studies are needed to assess the effects of PCSK9 inhibition on clinical outcomes. Trial Registration: clinicaltrials.gov Identifier: NCT01813422. SN - 1538-3598 UR - https://www.unboundmedicine.com/medline/citation/27846344/Effect_of_Evolocumab_on_Progression_of_Coronary_Disease_in_Statin_Treated_Patients:_The_GLAGOV_Randomized_Clinical_Trial_ L2 - https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2016.16951 DB - PRIME DP - Unbound Medicine ER -