Crestor vs Repatha: Head-to-Head Efficacy Comparison

The Two Drugs Act on Different Targets

Both labels describe a reduction in the risk of major adverse cardiovascular events in adults at increased risk, but the composites are defined differently and the trials behind them enrolled different populations [1][2].

Rosuvastatin inhibits HMG-CoA reductase, the rate-limiting enzyme that converts HMG-CoA to mevalonate, a cholesterol precursor [2]. Evolocumab binds PCSK9, a protein that normally binds the LDL receptor on liver cells and promotes its degradation; blocking that binding leaves more LDL receptors available to clear LDL cholesterol from the blood [1]. In LAPLACE-2, evolocumab was tested in 1,896 patients already taking atorvastatin, rosuvastatin or simvastatin, and the label reports its LDL effect against both placebo and ezetimibe 10 mg [1].

JUPITER: Rosuvastatin 20 mg Against Placebo

JUPITER enrolled 17,802 apparently healthy men aged 50 and older and women aged 60 and older with LDL cholesterol under 130 mg/dL and high-sensitivity C-reactive protein of 2.0 mg/L or higher [3]. They took rosuvastatin 20 mg daily or placebo, and the trial was stopped early at a median follow-up of 1.9 years [3].

The primary end point (myocardial infarction, stroke, arterial revascularization, hospitalization for unstable angina or cardiovascular death) occurred at 0.77 per 100 person-years on rosuvastatin and 1.36 per 100 person-years on placebo (HR 0.56, 95% CI 0.46 to 0.69) [3]. The Crestor label reports the same result as 142 versus 252 events, a 44% relative risk reduction and a 1.2% absolute risk reduction [2]. LDL cholesterol fell 50% and hsCRP fell 37% [3].

FOURIER: Evolocumab Added to a Statin

FOURIER enrolled 27,564 patients with established atherosclerotic cardiovascular disease and LDL cholesterol of 70 mg/dL or higher who were already receiving statin therapy; 69% were on a high-intensity statin, 81% had a prior myocardial infarction and 19% a prior stroke [4]. They received evolocumab 140 mg every 2 weeks or 420 mg monthly, or placebo, for a median of 2.2 years [4].

The primary composite (cardiovascular death, myocardial infarction, stroke, unstable angina hospitalization or coronary revascularization) occurred in 1,344 patients (9.8%) on evolocumab and 1,563 (11.3%) on placebo, HR 0.85 (95% CI 0.79 to 0.92) [4]. The key secondary composite of cardiovascular death, myocardial infarction or stroke was 816 (5.9%) versus 1,013 (7.4%), HR 0.80 (0.73 to 0.88) [4].

The label breaks the components out: myocardial infarction 468 versus 639 (HR 0.73), stroke 207 versus 262 (HR 0.79), coronary revascularization 759 versus 965 (HR 0.78), cardiovascular death 251 versus 240 (HR 1.05, 0.88 to 1.25) and all-cause death 444 versus 426 (HR 1.04, 0.91 to 1.19) [1].

LDL cholesterol fell 59% versus placebo at 48 weeks, from a median of 92 mg/dL to 30 mg/dL [4]. The label gives the difference as 63% at week 12 and 57% at week 72, with a median of 26 mg/dL at week 48 and 47% of patients below 25 mg/dL [1].

JUPITER enrolled people without cardiovascular disease who had an elevated hsCRP; FOURIER enrolled people who already had atherosclerotic disease and a median LDL of 92 mg/dL despite a statin [3][4]. Each result is a relative reduction against placebo from a different baseline, so the two figures do not show which drug lowers risk more.

Evolocumab in People Without a Prior Heart Attack or Stroke

VESALIUS-CV randomized 12,257 patients with atherosclerosis or diabetes and no prior myocardial infarction or stroke, LDL cholesterol 90 mg/dL or higher, to evolocumab 140 mg every 2 weeks or placebo for a median of 4.6 years [5]. Three-point MACE (coronary heart disease death, myocardial infarction or ischemic stroke) occurred in 336 patients (5-year Kaplan-Meier estimate 6.2%) versus 443 (8.0%), HR 0.75 (95% CI 0.65 to 0.86); four-point MACE, which adds ischemia-driven arterial revascularization, was 747 (13.4%) versus 907 (16.2%), HR 0.81 [5].

The Repatha label reports the same trial as 12,206 patients, with three-point MACE 5.5% versus 7.3% (HR 0.75) and four-point MACE 12.2% versus 14.8% (HR 0.81), plus all-cause death 432 versus 538 (HR 0.80, 0.70 to 0.90); coronary heart disease death (HR 0.90, 0.69 to 1.17) did not reach statistical significance and ischemic stroke HR 0.79 had a confidence interval of 0.62 to 1.01 [1].

How Much Each Drug Lowered LDL

Rosuvastatin 20 mg lowered LDL cholesterol by 50% in JUPITER [3], and rosuvastatin 40 mg lowered it by 49% in METEOR, from a mean of 155 mg/dL to 78 mg/dL [6]. Evolocumab lowered LDL by 59% versus placebo in FOURIER, on top of background statin therapy [4]. In LAPLACE-2 the differences versus placebo were 71% with 140 mg every 2 weeks and 63% with 420 mg monthly, and versus ezetimibe 10 mg they were 45% and 41% [1].

Plaque Imaging

GLAGOV randomized 968 patients with angiographic coronary disease who were on statins to evolocumab 420 mg monthly or placebo for 76 weeks, and measured percent atheroma volume in the coronary arteries by intravascular ultrasound: it increased 0.05% with placebo and decreased 0.95% with evolocumab (difference -1.0%, 95% CI -1.8 to -0.64) [7]. METEOR randomized 984 low-risk adults to rosuvastatin 40 mg or placebo for 2 years and measured maximum carotid intima-media thickness: the annualized change was -0.0014 mm/year versus +0.0131 mm/year (difference -0.0145 mm/year) [6].

Side Effects in the Labels

In the Crestor label's pooled placebo-controlled trials of up to 12 weeks (5 to 40 mg daily, N=744; placebo N=382): myalgia 2.8% versus 1.3%, headache 5.5% versus 5.0% and nausea 3.4% versus 3.1% [2]. In METEOR (40 mg, N=700; placebo N=281, mean 1.7 years) myalgia was 12.7% versus 12.1% and ALT above 3 times the upper limit of normal 2.2% versus 0.7% [2]. In JUPITER, myalgia was 7.6% versus 6.6%, diabetes mellitus was reported in 2.8% versus 2.3%, and mean HbA1c rose 0.1% more on rosuvastatin [2]. The label has no boxed warning; it warns about myopathy and rhabdomyolysis, lists age 65 or older, uncontrolled hypothyroidism, renal impairment, interacting drugs and higher dose as risk factors, and notes that Asian patients may be at higher risk [2].

In the Repatha label's 52-week placebo-controlled trial (420 mg monthly, N=599; placebo N=302): nasopharyngitis 10.5% versus 9.6%, injection-site reactions 5.7% versus 5.0%, myalgia 4.0% versus 3.0%, and discontinuation 2.2% versus 1.0% [1]. Across eight pooled controlled trials, injection-site reactions were 3.2% versus 3.0% and hypersensitivity reactions 5.1% versus 4.7% [1]. In FOURIER, the only adverse event that differed significantly between groups was injection-site reactions (2.1% versus 1.6%), and new-onset diabetes among people without diabetes at baseline was 8.1% versus 7.7% [4][1]. Binding antibodies developed in 0.3% (48 of 17,992), none neutralizing [1]. The label has no boxed warning; its only Warning and Precaution is hypersensitivity including angioedema, and it notes that some needle covers contain dry natural rubber [1].

Thinking and Memory

The EBBINGHAUS substudy of FOURIER followed 1,204 patients for a median of 19 months and found evolocumab non-inferior to placebo on the spatial working memory strategy index of executive function (mean change -0.21 versus -0.29, non-inferiority P<0.001); the label adds that it was also non-inferior on selected other cognitive domains [8][1].