New results suggest that evolocumab significantly reduced low-density lipoprotein cholesterol (LDL-C) levels at 24 weeks in patients with statin intolerance related to muscle-related adverse effects when compared with ezetimibe.
Researchers of the global, randomized GAUSS-3 trial, presented at the 2016 American College of Cardiology Scientific Sessions & Expo and published simultaneously in JAMA, aimed to compare the lipid-lowering efficacy of 2 nonstatin therapies—ezetimibe and evolocumab—in patients with muscle symptoms confirmed by statin rechallenge.
The study featured 511 adult patients who were enrolled in 2013 and 2014 and had uncontrolled LDL-C levels and a history of intolerance to 2 or more statins.
Researchers divided the study into 2 phases. In phase A, a 24-week crossover procedure with 20 mg atorvastatin or placebo was used to determine patients who had symptoms with atorvastatin, but not with placebo. And in phase B, patients were randomly assigned 2:1 to evolocumab (420 mg/monthly) or ezetimibe (10 mg/day) for 24 weeks following a 2-week washout.
The first coprimary endpoint was mean percent change in LDL-C level from baseline to the mean of weeks 22 and 24, and the second coprimary endpoint was LDL-C levels from baseline to 24 weeks.
Baseline characteristics for patients who entered phase A (n=491; 50% women) indicated a mean age of 60.7 years, a mean entry LDL-C level of 212.3 mg/dL, and 34.6% had coronary heart disease.
“These were people that everybody would agree needed to be treated, and yet they would not take a statin because of symptoms,” Steven E. Nissen, MD, study investigator from the Cleveland Clinic, said during a press conference.
Among phase A patients, 42.6% had muscle symptoms while taking atorvastatin, but not while taking placebo. Of these patients, 199 began phase B, along with 19 patients who proceeded directly to phase B for elevated creatine kinase, totaling 218 patients (entry mean LDL-C level, 219.9 mg/dL).
Seventy-three of the phase B patients were randomly assigned to ezetimibe, while the remaining 145 received evolocumab.
Data concerning the mean of weeks 22 and 24 indicated that LDL-C with ezetimibe was 183 mg/dL, mean percent LDL-C change was −16.7%, and absolute change was −31 mg/dL, whereas with evolocumab, the mean LDL-C was 103.6 mg/dL, mean percent change was −54.5%, and absolute change was −106.8 mg/dL (P<.001).
Analysis of the second coprimary endpoint resulted in similar findings. Specifically, at 24 weeks, LDL-C level with ezetimibe was 181.5 mg/dL, mean percent change was −16.7%, and absolute change was −31.2 mg/dL, and with evolocumab, the LDL-C level was 104.1 mg/dL, mean percent change was −52.8%, and absolute change was −102.9 mg/dL (P<.001).
In other data, muscle symptoms were observed in 28.8% of the ezetimibe arm and 20.7% of the evolocumab arm (P=.17), and the active study drug was stopped because of muscle symptoms in 6.8% of the ezetimibe group compared with 0.7% of the evolocumab group.
“What we learned is that you can document statin intolerance with this kind of rechallenge procedure; it is a real disorder,” Dr Nissen said. “The PCSK9 inhibitor … evolucumab can produce profound LDL reductions, greater than 50%, with almost no patients experiencing intolerable muscle symptoms on the alternative therapy.”
- Nissen SE. Late-Breaking Clinical Trials II. ￼The GAUSS-3 trial: goal achievement after utilizing an anti-PCSK9 antibody in statin intolerant subjects-3. Presented at the 65th Annual Scientific Session and Expo of the American College of Cardiology. April 2-4, 2016; Chicago, IL.
- Nissen SE, Stroes E, Dent-Acosta RE, et al. Efficacy and tolerability of evolocumab vs ezetimibe in patients with muscle-related statin intolerance: the GAUSS-3 randomized clinical trial. JAMA. 2016;doi:10.1001/jama.2016.3608.