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JAMA. 2016 Apr 19;315(15):1580-90. doi: 10.1001/jama.2016.3608.

Efficacy and Tolerability of Evolocumab vs Ezetimibe in Patients With Muscle-Related Statin Intolerance: The GAUSS-3 Randomized Clinical Trial.

Author information

1
Cleveland Clinic, Cleveland, Ohio.
2
University of Amsterdam Faculty of Medicine, Amsterdam, the Netherlands.
3
Amgen Inc, Thousand Oaks, California.
4
School of Medicine at Mount Sinai, New York, New York.
5
Flinders University, Bedford Park, SA, Australia.
6
University of Glasgow, Glasgow, United Kingdom.
7
Clinical Trial Service Unit, University of Oxford, Oxford, United Kingdom8Epidemiological Services Unit, University of Oxford, Oxford, United Kingdom.
8
University Hospital of Paris 6, Paris, France.
9
Charles University in Prague, Prague, Czech Republic11General University Hospital in Prague, Prague, Czech Republic.
10
David Geffen School of Medicine at the University of California, Los Angeles.
11
Baylor College of Medicine, Houston, Texas.
12
Center for Endocrinology, Diabetes and Preventive Medicine, University of Cologne, Cologne, Germany.
13
Metabolic and Atherosclerosis Research Center, Cincinnati, Ohio.

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, -31.0 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, -75.8 mg/dL. For week 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.

TRIAL REGISTRATION:

clinicaltrials.gov Identifier: NCT01984424.

PMID:
27039291
DOI:
10.1001/jama.2016.3608
[Indexed for MEDLINE]

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