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PCSK9 Inhibitors Lower Cholesterol for Statin Intolerant, But at What Cost?


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.”

 

References

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.

Waters DD, Hsue PY, Bangalore S. PCSK9 inhibitors for statin intolerance? [published online ahead of print April 3, 2016]. JAMA. doi:10.1001/jama.2016.3670.

 

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