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FOURIER Cardiovascular Outcomes Trial1,4:
Repatha® + statin (key secondary endpoint)

Demonstrated significant risk reduction in time to MI, stroke, or CV death, whichever occurred first vs. placebo + statin

Time to CV death was not statistically significant vs. placebo (p=0.6188)

Demonstrated 20% RRR in time to CV death, heart attack, or stroke HR 0.80 (95% CI: 0.73, 0.88; p < 0.0001; patients with event: Repatha® 5.92%, placebo 7.35%)

Graphic depiction of cumulative incidence estimates for key secondary endpoint over 3

Primary composite endpoint

Demonstrated 15% reduced risk in time to CV death, heart attack, stroke, hospitalization for unstable angina or coronary revascularization, whichever occurred first vs. placebo ( HR 0.85, 95% CI: 0.79, 0.92; p < 0.0001; patients with event: Repatha® 9.75%, placebo 11.34%).

Study Design Patient characteristics Publication download

FOURIER cardiovascular outcomes study design1,4,7

FOURIER study was designed to evaluate CV risk reduction with Repatha® + statin in high-risk patients with CVD

The FOURIER study was conducted in a wide range of patients with established CVD, including those with MI, stroke, and PAD

FOURIER: A multicentre, double-blind, randomized, placebo-controlled study

Screening
  • Age ≥ 40 to ≤ 85 years
  • Prior MI, prior stroke, or symptomatic PAD
  • Additional risk factors (≥ 1 major or > 2 minor)*
  • Stable background lipid-lowering therapy (including effective dose of statin ± ezetimibe)
  • LDL-C ≥ 1.8 mmol/L [70 mg/dL] or non-HDL-C ≥ 2.6 mmol/L [100 mg/dL]

MAX = 15 WEEKS

Graphic depiction of study

Median follow-up duration: 2.2 years (26 months)
Primary endpoint: Composite of time to first event of CV death, MI, stroke, hospitalization for unstable angina or coronary revascularization
Key secondary endpoint: Composite of time to first event of CV death, MI, or stroke

Publication download

* Patients were required to have at least one major CV risk factor, e.g., diabetes mellitus, current daily cigarette smoking, age ≥ 65 years or recent MI (within 6 months); or two or more minor risk factors, e.g., history of coronary revascularization, elevated non-HDL-C, metabolic syndrome.
CV=cardiovascular; CVD=cardiovascular disease; HDL-C=high-density lipoprotein cholesterol; LDL-C=low-density lipoprotein cholesterol; MI=myocardial infarction; PAD=peripheral artery disease; Q2W=every 2 weeks; Q2W=monthly.

FOURIER trial patient characteristics1,4

FOURIER included patients you often see in your waiting room—those at risk for another CV event

Parameter Patients (N = 27,564)
Baseline LDL-C, mmol/L
(median interquartile range) 		2.4 mmol/L
(2.1–2.8)
Baseline statin use High intensity
Moderate intensity 		69%
30%
Selected CV risk factors Hypertension
Type 2 diabetes mellitus
Current cigarette use 		80%
36%
28%
Previous CV event* MI
Nonhemorrhagic stroke
PAD 		81%
19%
13%
Ezetimibe use 5%
Other CV medications Antiplatelet agents
Beta-blocker
ACE inhibitor
ARB 		93%
76%
56%
23%
  • The FOURIER trial enrolled patients with a median baseline LDL-C of 2.4 mmol/L
  • ~70% of patients in the Repatha® arm were on high-intensity statins
Publication download

* Patients could have more than one type of previous CV event.
ACE=angiotensin converting enzyme; ARB=angiotensin II receptor blocker; CV=cardiovascular; LDL-C=low-density lipoprotein cholesterol; MI=myocardial infarction; PAD=peripheral artery disease.

LAPLACE-2 study: Powerful LDL-C reduction shown in patients with primary hyperlipidemia1,5

Overall study population included those with ASCVD

Repatha® Q2W + statin provided an additional 73% LDL-C reduction overall (vs. placebo + statin; p < 0.0001).*

Graphic depiction of reduction in LDL-C with Repatha

Prevention of Cardiovascular Events: Repatha® is indicated as an adjunct to diet and standard of care therapy (including moderate- to high-intensity statin therapy alone or in combination with other lipid-lowering therapy), to reduce the risk of myocardial infarction, stroke, and coronary revascularization in adult patients with atherosclerotic cardiovascular disease (ASCVD) by further lowering low-density lipoprotein cholesterol (LDL-C) levels.

Primary Hyperlipidemia (including Heterozygous Familial Hypercholesterolemia [HeFH] and ASCVD): Repatha® is indicated for the reduction of elevated low density lipoprotein cholesterol (LDL-C) in adult patients with primary hyperlipidemia (including heterozygous familial hypercholesterolemia and ASCVD): as an adjunct to diet and statin therapy, with or without other lipid-lowering therapies, in patients who require additional lowering of LDL-C; as an adjunct to diet, alone or in combination with non-statin lipid-lowering therapies, in patients for whom a statin is contraindicated.

Up to 95% of patients achieved LDL-C < 1.8 mmol/L with Repatha® (Q2W and QM doses).

Study Design Publication download

* Overall difference, mean % change from baseline to week 12 in LDL-C, mean difference from placebo with Repatha® 140 mg Q2W (95% CI: -77%, -70%; p < 0.0001).

LAPLACE-2 study design1,5

Phase 3, 12-week, randomized, double-blind, placebo- and ezetimibe-controlled trial (N=1,896) in patients with primary hyperlipidemia (including 526 who had ASCVD) on maximum dose statin therapy. Patients were initially randomized to an open-label specific statin regimen for a 4-week lipid-stabilization period followed by random assignment to Repatha® 140 mg Q2W, Repatha® 420 mg QM or placebo for 12 weeks as add-on to daily statin therapy. Baseline LDL-C 2.8 mmol/L, measured after the lipid stabilization period and before administration of first dose of Repatha®. Primary endpoint: Mean % change from baseline in LDL-C at week 12.

Publication download

RUTHERFORD-2 study: Powerful LDL-C reduction in high-risk patients with HeFH1,6

Graphic depiction of reduction in LDL-C with Repatha

Background therapy: statin ± other lipid-lowering therapy, at 12 weeks.

Repatha® provided 61% additional reduction in mean LDL-C vs. patients on background therapy alone.

Study Design Publication download HeFH Criteria

RUTHERFORD-2 study design1,6

Phase 3, 12-week, randomized, double-blind, placebo-controlled trial in patients with HeFH (diagnosed by the Simon Broome criteria) (N=329). Patients randomized to Repatha® 140 mg Q2W, Repatha ® 420 mg QM or placebo for 12 weeks. All patients were on a stable dose of statin, with or without other lipid-lowering therapies, and 76% were on high-intensity statin therapy. Average LDL-C at baseline 4.0 mmol/L.

Primary endpoint: Mean % change from baseline in LDL-C at week 12. Secondary endpoints included proportion of patients achieving LDL-C < 1.8 mmol/L.

Publication download

HeFH criteria: Canadian Cardiovascular Society 2014 Position Statement on Familial Hypercholesterolemia

A genetic condition that causes high levels of LDL-C and can be diagnosed using the Simon Broome or Dutch Lipid Clinic diagnostic criteria.8 HeFH is now understood to affect about 1 in 250 people in Canada and globally.9

Simon Broome HeFH criteria8

Definite FH diagnosis

1. A plasma measurement of either:
Total cholesterol > 7.5 mmol/L (adult patient) or > 6.7 mmol/L (child aged < 16 years) LDL-C > 4.9 mmol/L (adult patient) or > 4.0 mmol/L (child aged < 16 years)

PLUS

2. Tendon xanthomas in the patient or any of the patient’s 1st- or 2nd-degree relatives

OR

3. DNA-based evidence in the patient of an LDL receptor mutation or other FH-related gene mutation

Probable FH diagnosis

1. A plasma measurement of either:
Total cholesterol > 7.5 mmol/L (adult patient) or > 6.7 mmol/L (child aged < 16 years) LDL-C > 4.9 mmol/L (adult patient) or > 4.0 mmol/L (child aged < 16 years)

PLUS

2. Family history of myocardial infarction before the age of:

  • 50 years in any 2nd-degree relative
  • 60 years in a 1st-degree relative

OR

3. Family history of total cholesterol > 7.5 mmol/L in any 1st- or 2nd-degree relative

Dutch Lipid Clinic HeFH criteria8

Points Criteria Diagnosis
1. First-degree relative with premature cardiovascular disease
OR
LDL-C > 95ᵗʰ percentile
OR
Personal history of premature peripheral or cerebrovascular disease,
OR
LDL-C 4.01–4.89 mmol/L 		Definite FH (≥ 8 points)
2. First-degree relative with tendon xanthoma or corneal arcus
OR
First-degree relative child ( < 18 years) with LDL-C > 95ᵗʰ percentile
OR
Personal history of coronary artery disease 		Probable FH (6–7 points)
3. LDL-C 4.91–6.44 mmol/L
4. Presence of corneal arcus in patient < 45 years
5. LDL-C 6.46–8.51 mmol/L Possible FH (3–5 points)
6. Presence of a tendon xanthoma
7. LDL-C > 8.53 mmol/L
OR
Functional mutation in the LDL-R gene

FH=familial hypercholesterolemia; HeFH=heterozygous familial hypercholesterolemia; LDL-C=low-density lipoprotein cholesterol.
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