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Among patients with uncontrolled LDL cholesterol who experience muscle pain on at least two statins evolocumab (Repatha) achieved a greater reduction in LDL than ezetimibe (Zetia).

When treatment effect was averaged over two time points (22 weeks and 24 weeks) the mean reduction in LDL was 54.4% with PCSK9 treatment versus 16.7% with ezetimibe (absolute -106.8 versus -31.0 mg/dL P<0.001), , of the Cleveland Clinic, and colleagues reported online in the Journal of the American Medical Association.

The GAUSS-3 (Goal Achievement After Utilizing an Anti- PCSK9 Antibody in Statin Intolerant Subjects 3) identified 511 patients with uncontrolled LDL and a history of statin intolerance with muscle pain, importantly the intolerance was confirmed with placebo-controlled statin rechallenge with atorvastatin -- 42.6% of patients developed muscle pain on atorvastatin, but not on placebo.

"To our knowledge, the GAUSS-3 trial represents the largest and most comprehensive study using a blinded rechallenge procedure to assess the ability of patients with a history of muscle-related adverse effects to tolerate statins," the researchers pointed out.

The GAUSS -3 results were also reported as a late-breaking clinical trial at the American College of Cardiology meeting in Chicago.

The researchers randomized the confirmed statin intolerant patients (n=199) to subcutaneous evolocumab, 420 mg monthly or ezetimibe 10 mg/day. At baseline the average LDL was 213 mg/dL. After randomization, LDL levels were checked at 22 and 24 weeks.

Although LDL reductions were impressive, neither evolocumab nor ezetimibe treatment achieved optimal LDL levels, nor were muscle symptoms eliminated with these statin alternatives and persistent muscle symptoms were reported in 28.8% of ezetimibe-treated patients and 20.7% of evolocumab-treated patients (log-rank P=0.17). Moreover, 6.8% of the ezetimibe-treated patients and 0.7% of those on evolocumab stopped treatment for muscle symptoms.

"This result is not surprising," , of San Francisco General Hospital, and colleagues agreed in an editorial accompanying the paper, adding that "similar results have been reported with evolocumab or alirocumab in statin-intolerant patients in three previous trials, although in this trial Nissen et al followed a precise protocol that identified patients who were truly statin intolerant."

Waters and colleagues point out that PCSK9 drugs are not approved for treatment of statin intolerance and, despite their ability to produce dramatic reductions in LDL, "PCSK9 inhibitors have not yet been shown to reduce cardiovascular events."

But perhaps the greatest barrier to use of these drugs is cost. "A 1-year sup- ply of either alirocumab or evolocumab currently costs approximately $14 000.16," the editorialists wrote. "According to a recent analysis, using a 'willingness-to-pay' threshold of $50 000 per quality-adjusted life-year gained, 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."

That would be acceptable, they wrote, for high-risk patients, who experienced "intolerable muscle symptoms while taking even a low statin dose," but Waters and colleagues said that only about 1% of statin intolerant patients meet that criteria.

Nissen and colleagues concluded that the given the benefit demonstrated by evolocumab, further studies were warranted.

From the American Heart Association: