April 04, 2016
The GAUSS-3 trial showed that the PCSK9 inhibitor Repatha (evolocumab, Amgen Inc) resulted in a significantly greater reduction in low-density lipoprotein (LDL) cholesterol levels after 24 weeks vs Zetia (ezetimibe, Merck) among patients with a known statin intolerance due to muscle-related adverse effects. The results were presented Sunday at the American College of Cardiology 65th Scientific Session & Expo and simultaneously published online in the Journal of the American Medical Association (JAMA).
GAUSS-3 was a 2-stage randomized clinical trial conducted by Nissen and colleagues. In phase A, 491 patients with well-documented muscle-related adverse reactions to 2 or more statins were randomized to receive either atorvastatin (20 mg daily) or placebo for 10 weeks, followed by a 2-week washout, and followed by crossover to the alternate treatment for 10 weeks. Intolerable muscle-related symptoms developed in 42.6% of patients while taking atorvastatin but not while taking the placebo.
In phase B, 218 patients who had exhibited muscle-related adverse effects while taking atorvastatin but not while taking placebo, or who had experienced a 10-fold increase in creatine kinase levels after statin administration, were randomized 2:1 to subcutaneous evolocumab (420 mg monthly; n=145) or oral ezetimibe (10 mg daily; n=73). At 24 weeks, LDL-cholesterol levels were reduced by 52.8% with evolocumab vs 16.7% with ezetimibe. The researchers concluded that more studies are needed to assess the long-term safety and efficacy.
Although the findings from GAUSS-3 are favorable, an accompanying editorial in JAMA raised concern about using PCSK9 inhibitors in statin-intolerant patients. One argument is the cost for a small fraction of high-risk patients who are statin intolerant: the $14,000-per-year price tag for these drugs far exceeds the willingness to pay threshold. “A PCSK9 inhibitor would need to cost $2600 per year to be worthwhile for a statin-intolerant patient with cardiovascular disease and an LDL-level of 70 mg/dL or greater,” wrote Waters and colleagues.
The JAMA editorial noted evolocumab may be an option for those who experience muscle pains with statins; however, they said such uses should be limited. “A patient at very high risk for a cardiovascular event with intolerable muscle symptoms while taking even a low statin dose should be considered as a candidate for this treatment. Less than 1% of all ‘statin-intolerant’ patients might belong in this group at present. For other patients with statin intolerance, the appropriateness of the use of these agents is less clear.”
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 [published online ahead of print April 3, 2016]. JAMA. doi:10.1001/jama.2016.3608.