TY - JOUR
T1 - Efficacy and tolerability of evolocumab vs ezetimibe in patients with muscle-related statin intolerance
T2 - The GAUSS-3 randomized clinical trial
AU - GAUSS-3 Investigators
AU - Nissen, Steven E.
AU - Stroes, Erik
AU - Dent-Acosta, Ricardo E.
AU - Rosenson, Robert S.
AU - Lehman, Sam J.
AU - Sattar, Naveed
AU - Preiss, David
AU - Bruckert, Eric
AU - Češka, Richard
AU - Lepor, Norman
AU - Ballantyne, Christie M.
AU - Gouni-Berthold, Ioanna
AU - Elliott, Mary
AU - Brennan, Danielle M.
AU - Wasserman, Scott M.
AU - Somaratne, Ransi
AU - Scott, Rob
AU - Stein, Evan A.
AU - Sullivan, David
AU - Kostner, Karam
AU - Don Wauchope, Andrew
AU - Hartleib, Michael
AU - Baass, Alexis
AU - Bergeron, Jean
AU - Joy, Tisha
AU - Adamkova, Vera
AU - Blaha, Vladimir
AU - Jeppesen, Jorgen
AU - Jensen, Henrik Kjaerulf
AU - Krempf, Michel
AU - Bully, Chantal
AU - Bosiljanoff, Peter
AU - Steinhagen-Thiessen, Elisabeth
AU - Pintus, Paolo
AU - Borghi, Claudio
AU - Sampietro, Tiziana
AU - Vigna, Giovanni Battista
AU - Mannarino, Elmo
AU - Pozzi, Claudio
AU - Liem, Anho
AU - Van Leendert, Rudolf
AU - Scott, Russell
AU - Kjaernli, Thorbjorn
AU - Langslet, Gisle
AU - Jacovides, Andrew
AU - Klug, Eric
AU - Blom, Dirk
AU - Neely, Dermot
AU - Dawson, Charlotte
AU - Pokrywka, Gregory
N1 - Publisher Copyright:
Copyright © 2016 American Medical Association. All rights reserved.
PY - 2016/4/19
Y1 - 2016/4/19
N2 - Importance: Muscle-related statin intolerance is reported by 5%to 20%of patients. Objective: To identify patients with muscle symptoms confirmed by statin rechallenge and compare lipid-lowering efficacy for 2 nonstatin therapies, ezetimibe and evolocumab. Design, Setting, and Participants: Two-stage randomized clinical trial including 511 adult patients with uncontrolled low-density lipoprotein cholesterol (LDL-C) levels and history of intolerance to 2 or more statins enrolled in 2013 and 2014 globally. Phase A used a 24-week crossover procedure with atorvastatin or placebo to identify patients having symptoms only with atorvastatin but not placebo. In phase B, after a 2-week washout, patients were randomized to ezetimibe or evolocumab for 24 weeks. Interventions: Phase A: atorvastatin (20mg) vs placebo. Phase B: randomization 2:1 to subcutaneous evolocumab (420mg monthly) or oral ezetimibe (10mg daily). Main Outcome and Measures: Coprimary end pointswere the mean percent change in LDL-C level from baseline to the mean ofweeks 22 and 24 levels and from baseline toweek 24 levels. Results: Of the 491 patients who entered phase A (mean age, 60.7 [SD, 10.2] years; 246 women [50.1%]; 170 with coronary heart disease [34.6%]; entry mean LDL-C level, 212.3 [SD, 67.9]mg/dL), muscle symptoms occurred in 209 of 491 (42.6%) while taking atorvastatin but not while taking placebo. Of these, 199 entered phase B, along with 19 who proceeded directly to phase B for elevated creatine kinase (N = 218, with 73 randomized to ezetimibe and 145 to evolocumab; entry mean LDL-C level, 219.9 [SD, 72]mg/dL). For the mean ofweeks 22 and 24, LDL-C level with ezetimibe was 183.0 mg/dL; mean percent LDL-C change, -16.7%(95% CI, -20.5% to -12.9%), absolute change, -31.0 mg/dL and with evolocumab was 103.6 mg/dL; mean percent change, -54.5%(95% CI, -57.2% to -51.8%); absolute change, -106.8 mg/dL (P < .001). LDL-C level at week 24 with ezetimibe was 181.5 mg/dL; mean percent change, -16.7% (95% CI, -20.8% to -12.5%); absolute change, -31.2 mg/dL and with evolocumab was 104.1 mg/dL; mean percent change, -52.8% (95% CI, -55.8% to -49.8%); absolute change, -102.9 mg/dL (P < .001). For the mean of weeks 22 and 24, between-group difference in LDL-C was -37.8%; absolute difference, -75.8mg/dL. For week 24, between-group difference in LDL-C was -36.1%; absolute difference, -71.7 mg/dL. Muscle symptomswere reported in 28.8% of ezetimibe-treated patients and 20.7% of evolocumab-treated patients (log-rank P = .17). Active study drugwas stopped for muscle symptoms in 5 of 73 ezetimibe-treated patients (6.8%) and 1 of 145 evolocumab-treated patients (0.7%). Conclusions and Relevance: Among patients with statin intolerance related to muscle-related adverse effects, the use of evolocumab compared with ezetimibe resulted in a significantly greater reduction in LDL-C levels after 24 weeks. Further studies are needed to assess long-term efficacy and safety.
AB - Importance: Muscle-related statin intolerance is reported by 5%to 20%of patients. Objective: To identify patients with muscle symptoms confirmed by statin rechallenge and compare lipid-lowering efficacy for 2 nonstatin therapies, ezetimibe and evolocumab. Design, Setting, and Participants: Two-stage randomized clinical trial including 511 adult patients with uncontrolled low-density lipoprotein cholesterol (LDL-C) levels and history of intolerance to 2 or more statins enrolled in 2013 and 2014 globally. Phase A used a 24-week crossover procedure with atorvastatin or placebo to identify patients having symptoms only with atorvastatin but not placebo. In phase B, after a 2-week washout, patients were randomized to ezetimibe or evolocumab for 24 weeks. Interventions: Phase A: atorvastatin (20mg) vs placebo. Phase B: randomization 2:1 to subcutaneous evolocumab (420mg monthly) or oral ezetimibe (10mg daily). Main Outcome and Measures: Coprimary end pointswere the mean percent change in LDL-C level from baseline to the mean ofweeks 22 and 24 levels and from baseline toweek 24 levels. Results: Of the 491 patients who entered phase A (mean age, 60.7 [SD, 10.2] years; 246 women [50.1%]; 170 with coronary heart disease [34.6%]; entry mean LDL-C level, 212.3 [SD, 67.9]mg/dL), muscle symptoms occurred in 209 of 491 (42.6%) while taking atorvastatin but not while taking placebo. Of these, 199 entered phase B, along with 19 who proceeded directly to phase B for elevated creatine kinase (N = 218, with 73 randomized to ezetimibe and 145 to evolocumab; entry mean LDL-C level, 219.9 [SD, 72]mg/dL). For the mean ofweeks 22 and 24, LDL-C level with ezetimibe was 183.0 mg/dL; mean percent LDL-C change, -16.7%(95% CI, -20.5% to -12.9%), absolute change, -31.0 mg/dL and with evolocumab was 103.6 mg/dL; mean percent change, -54.5%(95% CI, -57.2% to -51.8%); absolute change, -106.8 mg/dL (P < .001). LDL-C level at week 24 with ezetimibe was 181.5 mg/dL; mean percent change, -16.7% (95% CI, -20.8% to -12.5%); absolute change, -31.2 mg/dL and with evolocumab was 104.1 mg/dL; mean percent change, -52.8% (95% CI, -55.8% to -49.8%); absolute change, -102.9 mg/dL (P < .001). For the mean of weeks 22 and 24, between-group difference in LDL-C was -37.8%; absolute difference, -75.8mg/dL. For week 24, between-group difference in LDL-C was -36.1%; absolute difference, -71.7 mg/dL. Muscle symptomswere reported in 28.8% of ezetimibe-treated patients and 20.7% of evolocumab-treated patients (log-rank P = .17). Active study drugwas stopped for muscle symptoms in 5 of 73 ezetimibe-treated patients (6.8%) and 1 of 145 evolocumab-treated patients (0.7%). Conclusions and Relevance: Among patients with statin intolerance related to muscle-related adverse effects, the use of evolocumab compared with ezetimibe resulted in a significantly greater reduction in LDL-C levels after 24 weeks. Further studies are needed to assess long-term efficacy and safety.
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U2 - 10.1001/jama.2016.3608
DO - 10.1001/jama.2016.3608
M3 - Article
C2 - 27039291
AN - SCOPUS:84964330289
SN - 0098-7484
VL - 315
SP - 1580
EP - 1590
JO - JAMA - Journal of the American Medical Association
JF - JAMA - Journal of the American Medical Association
IS - 15
ER -