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GAUSS-3: Evolocumab superior to ezetimibe for LDL reduction in statin-intolerant patients
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CHICAGO — Patients with statin intolerance due to muscle symptoms experienced greater LDL reduction on evolocumab than they did while on ezetimibe, according to new data from the GAUSS-3 trial presented at the American College of Cardiology Scientific Session.
“Controversy has surrounded the issue of statin-associated muscle symptoms because of large differences in the incidence of this disorder in randomized trials and observational studies,” Steven E. Nissen, MD, Cardiology Today Editorial Board member and chairman of the department of cardiovascular medicine at the Cleveland Clinic, said during a press conference. “The GAUSS-3 trial demonstrates that muscle-related [statin] intolerance is reproducible during blinded statin rechallenge in a substantial fraction — about 40% — of patients with a history of symptoms. Accordingly, development of alternative approaches to LDL reduction for these patients represents an important medical priority.”
Steven E. Nissen
Statin intolerance hard to define
The study was conducted in two double-blind phases to evaluate the efficacy and tolerability of the PCSK9 inhibitor evolocumab (Repatha, Amgen) vs. ezetimibe (Zetia, Merck) in patients with muscle-related statin intolerance during a 24-week follow-up.
“You can document statin intolerance. It is a real disorder,” Nissen said during the press conference.
Coprimary endpoints of the trial included the mean percent change in LDL level from baseline to the mean of weeks 22 and 24 levels, and from baseline to week 24 levels; and the percent change from baseline LDL to the level at week 24, which reflects effects at the end of the dosing interval.
In Phase A, patients from 53 centers were enrolled in a crossover study with atorvastatin 20 mg or placebo for ten weeks to identify which ones were having muscle symptoms with atorvastatin, but not placebo.
Phase B consisted of only those patients who had muscle symptoms on atorvastatin or creatinine kinase (CK) ≥ 10 times the upper limit of normal during statin treatment. Some patients proceeded directly to Phase B if they had a CK elevation that was 10 times the normal limit. Patients went through a 2-week washout period before entering Phase B.
In this phase, 218 patients (mean age, 60.7 years; 50.1% women; 34.6% with CHD) were randomized to either ezetimibe 10 mg/day or evolocumab 420 mg/month for 24 weeks. The results are simultaneously published in the Journal of the American Medical Association.
Evolocumab vs. ezetimibe
Of the 491 patients enrolled in Phase A, 42.6% of them had muscle symptoms on atorvastatin and 26.5% had them on placebo. The researchers found that 9.8% of patients had symptoms on both placebo and atorvastatin and 17.3% had no symptoms at all.
In Phase B, muscle-related symptoms were reported in 28.8% of patients on ezetimibe and 20% of patients on evolocumab (log-rank P = .17).
For the mean of weeks 22 and 24, patients on ezetimibe had a LDL of 183 mg/dL (mean percent LDL cholesterol change, –16.7%; 95% CI, –20.5% to –12.9%, absolute change, –31.0 mg/dL). The LDL of patients on 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.
“There were some muscle symptoms reported on evolocumab, but in only 1 out of the 145 patients assigned to it did it lead them to discontinue the trial, which is very encouraging,” Nissen said.
Nissen suggested that a treatment of ezetimibe combined with evolocumab might be worth investigating, given that most of the patients did not reach optimal LDL on evolocumab alone.
Nissen acknowledged that without a biomarker test, it is difficult to be certain of a statin intolerance diagnosis, but he said he feels strongly that alternatives needed to be provided to patients.
“When a patient looks you in the eye and says, ’I won’t take statin,’ you need to provide other alternatives,” he said. “I am pretty confident that the outcome trials will be successful. I would prescribe evolocumab to my patients at high risk.”– by Tracey Romero
Reference:
Nissen S, et al. Joint ACC/JACC Late-Breaking Clinical Trials. Presented at: American College of Cardiology Scientific Session; April 2-4, 2016; Chicago.
Nissen S, et al. JAMA. 2016; doi:10.1001/jama.2016.3608.
Disclosure: The GAUSS-3 trial was funded by Amgen. Nissen reports funding from Amgen, AstraZeneca, Eli Lilly, Esperion, Novartis, Novo Nordisk, Orexigen, Pfizer, Takeda and The Medicines Company. Please see full study for list of all other authors’ relevant financial disclosures.