Universität zu Köln

Nissen, Steven E., Stroes, Erik, Dent-Acosta, Ricardo E., Rosenson, Robert S., Lehman, Sam J., Sattar, Naveed, Preiss, David ORCID: 0000-0003-3139-1836, Bruckert, Eric, Ceska, Richard ORCID: 0000-0002-2541-5179, Lepor, Norman, Ballantyne, Christie M., Gouni-Berthold, Ioanna, Elliott, Mary, Brennan, Danielle M., Wasserman, Scott M., Somaratne, Ransi, Scott, Rob and Stein, Evan A. (2016). Efficacy and Tolerability of Evolocumab vs Ezetimibe in Patients With Muscle-Related Statin Intolerance The GAUSS-3 Randomized Clinical Trial. JAMA-J. Am. Med. Assoc., 315 (15). S. 1580 - 1591. CHICAGO: AMER MEDICAL ASSOC. ISSN 1538-3598

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Abstract

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 (20 mg) vs placebo. Phase B: randomization 2: 1 to subcutaneous evolocumab (420 mg monthly) or oral ezetimibe (10 mg daily). MAIN OUTCOME AND MEASURES Coprimary end points were the mean percent change in LDL-C level from baseline to the mean of weeks 22 and 24 levels and from baseline to week 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 of weeks 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, -31.0mg/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 181.5mg/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, -75.8 mg/dL. Forweek 24, between-group difference in LDL-C was -36.1%; absolute difference, -71.7 mg/dL. Muscle symptoms were reported in 28.8% of ezetimibe-treated patients and 20.7% of evolocumab-treated patients (log-rank P=.17). Active study drug was 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Nissen, Steven E. UNSPECIFIED UNSPECIFIED UNSPECIFIED Stroes, Erik UNSPECIFIED UNSPECIFIED UNSPECIFIED Dent-Acosta, Ricardo E. UNSPECIFIED UNSPECIFIED UNSPECIFIED Rosenson, Robert S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Lehman, Sam J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Sattar, Naveed UNSPECIFIED UNSPECIFIED UNSPECIFIED Preiss, David UNSPECIFIED orcid.org/0000-0003-3139-1836 UNSPECIFIED Bruckert, Eric UNSPECIFIED UNSPECIFIED UNSPECIFIED Ceska, Richard UNSPECIFIED orcid.org/0000-0002-2541-5179 UNSPECIFIED Lepor, Norman UNSPECIFIED UNSPECIFIED UNSPECIFIED Ballantyne, Christie M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Gouni-Berthold, Ioanna UNSPECIFIED UNSPECIFIED UNSPECIFIED Elliott, Mary UNSPECIFIED UNSPECIFIED UNSPECIFIED Brennan, Danielle M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Wasserman, Scott M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Somaratne, Ransi UNSPECIFIED UNSPECIFIED UNSPECIFIED Scott, Rob UNSPECIFIED UNSPECIFIED UNSPECIFIED Stein, Evan A. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-278491
DOI:	10.1001/jama.2016.3608
Journal or Publication Title:	JAMA-J. Am. Med. Assoc.
Volume:	315
Number:	15
Page Range:	S. 1580 - 1591
Date:	2016
Publisher:	AMER MEDICAL ASSOC
Place of Publication:	CHICAGO
ISSN:	1538-3598
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language MONOCLONAL-ANTIBODY; COMBINATION; CHOLESTEROL; ALIROCUMAB; SAFETY; PCSK9; MG Multiple languages Medicine, General & Internal Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/27849