Practice Update: Cardiology

AMERICAN COLLEGE OF CARDIOLOGY SCIENTIFIC SESSIONS 8

Evolocumab proven superior to ezetimibe in lowering cholesterol

S teven Nissen, MD, MACC, of the Cleveland Clinic, explained, “Statin intolerance has been one of the most vexing problems faced by cardiologists. Patients with high levels of LDL cholesterol and high risk of cardiovascular events are often reluctant or unwilling to take statins. This situation is extremely frustrating for both patients and physicians because there have not been good alternatives for treatment.” The prevalence of muscle-related statin intolerance is debated: large randomised trials have reported low rates of muscle symptoms, while observational studies have suggested that 5 to 20% of patients experience muscle symptoms. The phase 3, randomised, double-blind Goal Achievement after Utilizing an anti-PCSK9 antibody in Statin-intolerant Subjects (GAUSS) 3 trial enrolled 511 patients at 53 centres. Their LDL cholesterol averaged >210 mg/dL (5.44 mmol/L). Eighty two percent had tried and failed to tolerate three or more statins. A total of 42.6% of 491 patients who had previously reported muscle pain with at least two different statins had a recurrence of symptoms during blinded administration of atorvastatin, but not while taking placebo. More than a quarter, 26.5%, reported muscle pain while taking placebo but not while taking atorvastatin, suggesting that though statin intolerance can be confirmed in a substantial proportion of patients with self- reported intolerance, a significant proportion experience muscle pain that cannot be attributed to statins. After the initial phase, 218 patients with confirmed statin intolerance were enrolled in the second segment, with 145 randomised to evolocumab and 73 to ezetimibe. Participants in the second phase had an average baseline LDL cholesterol of 220 mg/dL (5.7 mmol/L). After 24 weeks of treatment with either evolucumab or ezetimibe, patients with confirmed statin intolerance who were given evolocumab showed an average 52.8% reduction in LDL cholesterol, a coprimary

The first major clinical trial to include a blinded, placebo- controlled “statin rechallenge” in patients with a history of muscle-related side effects has shed new light on statin- associated muscle symptoms. The trial also demonstrated that monthly self-injection of the nonstatin cholesterol- lowering agent evolocumab reduced levels of low density lipoprotein (LDL) cholesterol more than ezetimibe, a drug used in statin-intolerant patients. These findings were reported at the ACC 2016.

endpoint, vs a 16.7% reduction in those taking ezetimibe. For the study’s other coprimary endpoint, average change in LDL cholesterol for weeks 22 and 24, patients taking evolocumab showed a reduction of 54.5%, and those taking ezetimibe, a 16.7% reduction. After 24 weeks, those given evolocumab exhibited an average LDL cholesterol level of 104 mg/dL (2.69 mmol/L); 64.1% of patients taking evolocumab finished the trial with LDL cholesterol below 100 mg/dL (2.69 mmol/L), and 29.9% finished below 70 mg/ dL (2.69 mmol/L). One patient receiving evolocumab and five given ezetimibe discontinued due to muscle- related adverse events. Dr Nissen said, “The findings provide unique insights into the challenging clinical problem of muscle symptoms in statin treated patients. Evolocumab lowered LDL cholesterol substantially with few patients experiencing muscle symptoms.” He added, “The study carries important implications for both guidelines and regulatory policy, because it provides strong evidence that muscle-related statin intolerance is a real and reproducible phenomenon.” The study was limited by modest size and short duration, but Dr Nissen stated it was adequately powered to address its primary endpoint.

The study carries important implications for both guidelines and regulatory policy, because it provides strong evidence that muscle-related statin intolerance is a real and reproducible phenomenon.

PRACTICEUPDATE CARDIOLOGY