Lipid-efficacy RCT · Lancet 2015
RUTHERFORD-2 trial
PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial.
The bottom line
In patients with heterozygous familial hypercholesterolaemia on stable lipid-lowering therapy, adding evolocumab produced rapid, large LDL cholesterol reductions of about 60% compared with placebo with a tolerability profile similar to placebo.
Primary lipid endpoint metUS status: US-approved
At a glance
- Medicine
- Evolocumab (AMG 145) 140 mg subcutaneous every 2 weeks (n=111) or 420 mg monthly (n=110)
- Compared with
- Subcutaneous placebo every 2 weeks (n=55) or monthly (n=55)
- People
- 331
- Who took part
- Patients 18-80 years of age meeting clinical criteria for heterozygous familial hypercholesterolaemia, on stable lipid-lowering therapy for at least 4 weeks, with fasting LDL cholesterol concentration of 2·6 mmol/L or higher
- Design
- multicentre, randomised, double-blind, placebo-controlled trial
- Follow-up
- 12 weeks
- Main question
- Percentage change from baseline in LDL cholesterol at week 12 and at the mean of weeks 10 and 12
Main result
Compared with placebo, evolocumab at both dosing schedules led to a significant reduction in mean LDL cholesterol at week 12 (every-2-weeks dose: 59·2% reduction [95% CI 53·4-65·1], monthly dose: 61·3% reduction [53·6-69·0]; both p<0·0001) and at the mean of weeks 10 and 12 (60·2% reduction [95% CI 54·5-65·8] and 65·6% reduction [59·8-71·3]; both p<0·0001)
Effect on LDL cholesterol
59·2% reduction (every-2-weeks dose, week 12) and 61·3% reduction (monthly dose, week 12); 60·2% and 65·6% reduction at mean of weeks 10 and 12, respectively
Safety
Evolocumab was well tolerated, with rates of adverse events similar to placebo. The most common adverse events occurring more frequently in the evolocumab-treated patients than in the placebo groups were nasopharyngitis (in 19 patients [9%] vs five [5%] in the placebo group) and muscle-related adverse events (ten patients [5%] vs 1 [1%]).
In the trial's own words
“Compared with placebo, evolocumab at both dosing schedules led to a significant reduction in mean LDL cholesterol at week 12 (every-2-weeks dose: 59·2% reduction [95% CI 53·4-65·1], monthly dose: 61·3% reduction [53·6-69·0]; both p<0·0001) and at the mean of weeks 10 and 12 (60·2% reduction [95% CI 54·5-65·8] and 65·6% reduction [59·8-71·3]; both p<0·0001).”
Quoted from the abstract of Lancet 2015, checked word for word against PubMed. PubMed 25282519 · Full paper (DOI)
How this medicine works, where it stands and what it costs: Evolocumab (Repatha) and alirocumab (Praluent)
Common questions
What did the RUTHERFORD-2 trial find?
In patients with heterozygous familial hypercholesterolaemia on stable lipid-lowering therapy, adding evolocumab produced rapid, large LDL cholesterol reductions of about 60% compared with placebo with a tolerability profile similar to placebo.
Who was in RUTHERFORD-2?
331 people. Patients 18-80 years of age meeting clinical criteria for heterozygous familial hypercholesterolaemia, on stable lipid-lowering therapy for at least 4 weeks, with fasting LDL cholesterol concentration of 2·6 mmol/L or higher.
What was RUTHERFORD-2's main result?
Compared with placebo, evolocumab at both dosing schedules led to a significant reduction in mean LDL cholesterol at week 12 (every-2-weeks dose: 59·2% reduction [95% CI 53·4-65·1], monthly dose: 61·3% reduction [53·6-69·0]; both p<0·0001) and at the mean of weeks 10 and 12 (60·2% reduction [95% CI 54·5-65·8] and 65·6% reduction [59·8-71·3]; both p<0·0001)
How much did LDL cholesterol change in RUTHERFORD-2?
59·2% reduction (every-2-weeks dose, week 12) and 61·3% reduction (monthly dose, week 12); 60·2% and 65·6% reduction at mean of weeks 10 and 12, respectively
Related trials
- ODYSSEY ALTERNATIVE (2015)In statin-intolerant patients, alirocumab lowered LDL-C far more than ezetimibe and caused fewer muscle-related adverse events than statin rechallenge with atorvastatin.
- ODYSSEY FH I and II (2015)In patients with heterozygous familial hypercholesterolemia inadequately controlled on maximally tolerated lipid-lowering therapy, adding alirocumab produced large, durable LDL-C reductions through 78 weeks and was generally well tolerated.
- ODYSSEY LONG TERM (2015)Adding alirocumab to maximally tolerated statin therapy markedly lowered LDL cholesterol and was associated with a post hoc reduction in cardiovascular events, though with somewhat higher rates of injection-site reactions, myalgia, neurocognitive, and ophthalmologic events.
- TESLA Part B (2015)In patients with homozygous familial hypercholesterolaemia on stable background therapy, adding evolocumab 420 mg every 4 weeks significantly lowered LDL cholesterol compared with placebo and was well tolerated over 12 weeks.
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