INTERVENTION: Product Name: Evolocumab Product Code: AMG 145 Pharmaceutical Form: Solution for injection in pre‐filled pen INN or Proposed INN: Evolocumab Current Sponsor code: AMG 145 Concentration unit: mg/ml milligram(s)/millilitre Concentration type: equal Concentration number: 140‐ Pharmaceutical form of the placebo: Solution for injection in pre‐filled pen Route of administration of the placebo: Subcutaneous use Product Name: Evolocumab Product Code: AMG 145 Pharmaceutical Form: Solution for injection in cartridge INN or Proposed INN: Evolocumab Current Sponsor code: AMG 145 Concentration unit: mg/ml milligram(s)/millilitre Concentration type: equal Concentration number: 120‐ Pharmaceutical form of the placebo: Solution for injection in cartridge Route of administration of the placebo: Subcutaneous use CONDITION: Dyslipidemia ; MedDRA version: 18.1 Level: LLT Classification code 10020604 Term: Hypercholesterolemia System Organ Class: 100000004861 ; MedDRA version: 18.1 Level: LLT Classification code 10058110 Term: Dyslipidemia System Organ Class: 100000004861 Therapeutic area: Diseases [C] ‐ Nutritional and Metabolic Diseases [C18] PRIMARY OUTCOME: Main Objective: To evaluate the effect of treatment with evolocumab, compared with placebo, on the risk for cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization, whichever occurs first, in subjects with clinically evident cardiovascular disease. Primary end point(s): The primary endpoint is the time to cardiovascular death, myocardial infarction, hospitalization for unstable angina, stroke, or coronary revascularization, whichever occurs first. (Note: The primary endpoint includes all adjudicated strokes, ischemic and hemorrhagic.) Secondary Objective: Secondary objectives are to evaluate the effect of treatment with evolocumab, compared with placebo, in subjects with clinically evident cardiovascular disease on the risk for:; • cardiovascular death, myocardial infarction, or stroke; • cardiovascular death; • death by any cause; • myocardial infarction; • stroke; • Coronary revascularization; • cardiovascular death or hospital admissions for worsening heart failure; • fatal or non‐fatal ischemic stroke or transient ischemic attack (TIA); Timepoint(s) of evaluation of this end point: The primary endpoint is the time to cardiovascular death, myocardial infarction, hospitalization for unstable angina, stroke, or coronary revascularization, whichever occurs first. (Note: The primary endpoint includes all adjudicated strokes, ischemic and hemorrhagic.) SECONDARY OUTCOME: Secondary end point(s): Secondary endpoints are: ; • time to cardiovascular death, myocardial infarction, or stroke, whichever occurs first ; • time to cardiovascular death ; • time to death by any cause ; • time to first myocardial infarction ; • time to first stroke ; • time to first coronary revascularization ; • time to cardiovascular death or first hospitalization for worsening heart failure, whichever occurs first ; • time to ischemic fatal or non‐fatal stroke or TIA, whichever occurs first Timepoint(s) of evaluation of this end point: •time to cardiovascular death, myocardial infarction, or stroke, whichever occurs first ; • time to cardiovascular death ; • time to death by any cause ; • time to first myocardial infarction ; • time to first stroke ; • time to first coronary revascularization ; • time to cardiovascular death or first hospitalization for worsening heart failure, whichever occurs first ; • time to ischemic fatal or non‐fatal stroke or TIA, whichever occurs first INCLUSION CRITERIA: 4.1.1 Signed informed consent 4.1.2 Male or female = 40 to = 85 years of age at signing of informed consent 4.1.3 History of clinically evident cardiovascular disease as evidenced by ANY of the following: o diagnosis of myocardial infarction o diagnosis of non‐hemorrhagic stroke (TIA does not qualify as stroke for inclusion) o symptomatic peripheral arterial disease (PAD), as evidenced by intermittent claudication with ankle‐brachial index (ABI) < 0.85, or peripheral arterial revascularization procedure, or amputation due to atherosclerotic disease Note: the proportion of subjects with history of MI or nonhemorrhagic stroke > 5 years prior to screening will be determined by the sponsor 4.1.4 At least 1 major risk factor or at least 2 minor risk factors below: Major Risk Factors (1 Required): o diabetes (type 1 or type 2) o age = 65 years at randomization (and = 85 years at time of informed consent) o MI or non‐hem
The primary objective was to evaluate the effect of treatment with evolocumab, compared with placebo, on the risk for cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization, whichever occurs first, in patients with clinically evident cardiovascular disease.
BACKGROUND: Evolocumab is a monoclonal antibody that inhibits proprotein convertase subtilisin-kexin type 9 (PCSK9) and lowers low-density lipoprotein (LDL) cholesterol levels by approximately 60%. Whether it prevents cardiovascular events is uncertain.
METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving 27,564 patients with atherosclerotic cardiovascular disease and LDL cholesterol levels of 70 mg per deciliter (1.8 mmol per liter) or higher who were receiving statin therapy. Patients were randomly assigned to receive evolocumab (either 140 mg every 2 weeks or 420 mg monthly) or matching placebo as subcutaneous injections. The primary efficacy end point was the composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization. The key secondary efficacy end point was the composite of cardiovascular death, myocardial infarction, or stroke. The median duration of follow-up was 2.2 years.
RESULTS: At 48 weeks, the least-squares mean percentage reduction in LDL cholesterol levels with evolocumab, as compared with placebo, was 59%, from a median baseline value of 92 mg per deciliter (2.4 mmol per liter) to 30 mg per deciliter (0.78 mmol per liter) (P<0.001). Relative to placebo, evolocumab treatment significantly reduced the risk of the primary end point (1344 patients [9.8%] vs. 1563 patients [11.3%]; hazard ratio, 0.85; 95% confidence interval [CI], 0.79 to 0.92; P<0.001) and the key secondary end point (816 [5.9%] vs. 1013 [7.4%]; hazard ratio, 0.80; 95% CI, 0.73 to 0.88; P<0.001). The results were consistent across key subgroups, including the subgroup of patients in the lowest quartile for baseline LDL cholesterol levels (median, 74 mg per deciliter [1.9 mmol per liter]). There was no significant difference between the study groups with regard to adverse events (including new-onset diabetes and neurocognitive events), with the exception of injection-site reactions, which were more common with evolocumab (2.1% vs. 1.6%).
CONCLUSIONS: In our trial, inhibition of PCSK9 with evolocumab on a background of statin therapy lowered LDL cholesterol levels to a median of 30 mg per deciliter (0.78 mmol per liter) and reduced the risk of cardiovascular events. These findings show that patients with atherosclerotic cardiovascular disease benefit from lowering of LDL cholesterol levels below current targets. (Funded by Amgen; FOURIER ClinicalTrials.gov number, NCT01764633 .).
<b>BACKGROUND: </b>The FOURIER trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Patients With Elevated Risk) recently showed that the PCSK9 (proprotein convertase subtilisin-kexin type 9) inhibitor evolocumab significantly reduced major vascular events in patients with stable atherosclerotic cardiovascular disease, including patients with prior myocardial infarction (MI). Within the broad group of patients with prior MI, we hypothesized that readily ascertainable features would identify subsets who derive greater clinical risk reduction with evolocumab.<b>METHODS: </b>The 22 351 patients with a prior MI were characterized on the basis of time from most recent MI, number of prior MIs, and presence of residual multivessel coronary artery disease (≥40% stenosis in ≥2 large vessels). The relative and absolute risk reductions in major vascular events, including the primary end point (cardiovascular death, MI, stroke, hospitalization for unstable angina, or coronary revascularization) and the key secondary end point (cardiovascular death, MI, or stroke), with evolocumab in these subgroups were compared.<b>RESULTS: </b>A total of 8402 patients (38%) were within 2 years of their most recent MI; 5285 patients (24%) had ≥2 prior MIs; and 5618 patients (25%) had residual multivessel coronary artery disease. In a multivariable-adjusted model that simultaneously included all 3 high-risk features and other baseline covariates, more recent MI, multiple prior MIs, and residual multivessel coronary disease remained independent predictors of cardiovascular outcomes, with adjusted hazard ratios (HRs) for the primary end point of 1.37 (95% confidence interval [CI],1.22-1.53), 1.78 (95% CI, 1.59-1.99), and 1.39 (95% CI, 1.24-1.56; all P<0.001). The relative risk reductions with evolocumab for the primary end point tended to be greater in the high-risk subgroups and were 20% (HR, 0.80; 95% CI, 0.71-0.91), 18% (HR, 0.82; 95% CI, 0.72-0.93), and 21% (HR, 0.79; 95% CI, 0.69-0.91) for those with more recent MI, multiple prior MIs, and residual multivessel coronary artery disease, whereas they were 5% (HR, 0.95; 95% CI, 0.85-1.05), 8% (HR, 0.92; 95% CI, 0.84-1.02), and 7% (HR, 0.93; 95% CI, 0.85-1.02) in those without, respectively. Given the higher baseline risk, the respective absolute risk reductions at 3 years exceeded 3% in the high-risk groups (3.4%, 3.7%, and 3.6%) versus ≈1% in the low-risk groups (0.8%, 1.3%, and 1.2%).<b>CONCLUSIONS: </b>Patients closer to their most recent MI, with multiple prior MIs, or with residual multivessel coronary artery disease are at high risk for major vascular events and experience substantial risk reductions with low-density lipoprotein cholesterol lowering with evolocumab.<b>Clinical Trial Registration: </b>URL: https://www.clinicaltrials.gov . Unique identifier: NCT01764633.
<b>BACKGROUND: </b>Lipoprotein(a) [Lp(a)] may play a causal role in atherosclerosis. PCSK9 (proprotein convertase subtilisin/kexin 9) inhibitors have been shown to significantly reduce plasma Lp(a) concentration. However, the relationship between Lp(a) levels, PCSK9 inhibition, and cardiovascular risk reduction remains undefined.<b>METHODS: </b>Lp(a) was measured in 25 096 patients in the FOURIER trial (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk), a randomized trial of evolocumab versus placebo in patients with established atherosclerotic cardiovascular disease (median follow-up, 2.2 years). Cox models were used to assess the independent prognostic value of Lp(a) and the efficacy of evolocumab for coronary risk reduction by baseline Lp(a) concentration.<b>RESULTS: </b>The median (interquartile range) baseline Lp(a) concentration was 37 (13-165) nmol/L. In the placebo arm, patients with baseline Lp(a) in the highest quartile had a higher risk of coronary heart disease death, myocardial infarction, or urgent revascularization (adjusted hazard ratio quartile 4: quartile 1, 1.22; 95% CI, 1.01-1.48) independent of low-density lipoprotein cholesterol. At 48 weeks, evolocumab significantly reduced Lp(a) by a median (interquartile range) of 26.9% (6.2%-46.7%). The percent change in Lp(a) and low-density lipoprotein cholesterol at 48 weeks in patients taking evolocumab was moderately positively correlated ( r=0.37; 95% CI, 0.36-0.39; P<0.001). Evolocumab reduced the risk of coronary heart disease death, myocardial infarction, or urgent revascularization by 23% (hazard ratio, 0.77; 95% CI, 0.67-0.88) in patients with a baseline Lp(a) >median, and by 7% (hazard ratio, 0.93; 95% CI, 0.80-1.08; P interaction=0.07) in those ≤median. Coupled with the higher baseline risk, the absolute risk reductions, and number needed to treat over 3 years were 2.49% and 40 versus 0.95% and 105, respectively.<b>CONCLUSIONS: </b>Higher levels of Lp(a) are associated with an increased risk of cardiovascular events in patients with established cardiovascular disease irrespective of low-density lipoprotein cholesterol. Evolocumab significantly reduced Lp(a) levels, and patients with higher baseline Lp(a) levels experienced greater absolute reductions in Lp(a) and tended to derive greater coronary benefit from PCSK9 inhibition.<b>Clinical Trial Registration: </b>URL: https://www.clinicaltrials.gov . Unique identifier: NCT01764633.
Background: Concerns have been raised about low LDL‐C levels and possible adverse effects on cognition. PCSK9 inhibitors markedly lower LDL‐C, yet EBBINGHAUS, a prespecified substudy within the FOURIER trial, did not show adverse cognitive changes with evolocumab over 19 months median follow‐up. Purpose: To investigate the long‐term effects of evolocumab on cognitive function. Methods: EBBINGHAUS was a substudy of cognitive function using the Cambridge Neuropsychological Test Automated Battery (CANTAB) within the FOURIER randomized trial of evolocumab vs placebo in patients with established ASCVD. Patients in North America and Europe who completed EBBINGHAUS on study drug were eligible for an open‐label extension (OLE) study with evolocumab. The primary endpoint was change in spatial working memory strategy index of executive function score (SWMI) from baseline over time. Secondary endpoints were measures of working memory, episodic memory, and psychomotor speed. A paired t‐test was used to compare baseline vs post‐baseline scores during OLE. Results: Of 1204 patients from EBBINGHAUS, 306 entered the OLE and were treated with evolocumab for a median of 5.1 years. Median achieved LDL‐C was 34 mg/dL (IQR 21‐50). No significant change in SWMI occurred during the OLE period overall [mean (±SD) change ‐0.1±2.7, p=0.73] or when stratified by original randomized allocation (Figure 1A). For secondary outcomes, one showed no change during the OLE period, two showed small changes (10‐15% of SD), but these were directionally inconsistent (one higher, one lower). In 152 patients originally randomized to evolocumab, there was no significant change in SWMI from randomization through long‐term follow‐up over a median of 6.7 and a maximum of 7.2 years (mean change 0.1±2.6, p=0.66) (Figure 1B). Conclusion: Evolocumab did not lead to any apparent long‐term decline in cognitive function through follow‐up extending up to 7.2 years. (Figure Presented).
Product Name: Evolocumab Product Code: AMG 145 Pharmaceutical Form: Solution for injection in pre‐filled pen INN or Proposed
INN:
Evolocumab Current Sponsor code: AMG 145 Concentration unit: mg/ml milligram(s)/millilitre Concentration type: equal Concentration number: 140‐ Pharmaceutical form of the placebo: Solution for injection in pre‐filled pen Route of administration of the placebo: Subcutaneous use Product Name: Evolocumab Product Code: AMG 145 Pharmaceutical Form: Solution for injection in cartridge INN or Proposed
INN:
Evolocumab Current Sponsor code: AMG 145 Concentration unit: mg/ml milligram(s)/millilitre Concentration type: equal Concentration number: 120‐ Pharmaceutical form of the placebo: Solution for injection in cartridge Route of administration of the placebo: Subcutaneous use
CONDITION:
Dyslipidemia ; MedDRA version: 18.1 Level: LLT Classification code 10020604 Term: Hypercholesterolemia System Organ Class: 100000004861 ; MedDRA version: 18.1 Level: LLT Classification code 10058110 Term: Dyslipidemia System Organ Class: 100000004861 Therapeutic area: Diseases [C] ‐ Nutritional and Metabolic Diseases [C18]
PRIMARY OUTCOME:
Main Objective: To evaluate the effect of treatment with evolocumab, compared with placebo, on the risk for cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization, whichever occurs first, in subjects with clinically evident cardiovascular disease. Primary end point(s): The primary endpoint is the time to cardiovascular death, myocardial infarction, hospitalization for unstable angina, stroke, or coronary revascularization, whichever occurs first. (Note: The primary endpoint includes all adjudicated strokes, ischemic and hemorrhagic.) Secondary Objective: Secondary objectives are to evaluate the effect of treatment with evolocumab, compared with placebo, in subjects with clinically evident cardiovascular disease on the risk for:; • cardiovascular death, myocardial infarction, or stroke; • cardiovascular death; • death by any cause; • myocardial infarction; • stroke; • Coronary revascularization; • cardiovascular death or hospital admissions for worsening heart failure; • fatal or non‐fatal ischemic stroke or transient ischemic attack (TIA); Timepoint(s) of evaluation of this end point: The primary endpoint is the time to cardiovascular death, myocardial infarction, hospitalization for unstable angina, stroke, or coronary revascularization, whichever occurs first. (Note: The primary endpoint includes all adjudicated strokes, ischemic and hemorrhagic.)
SECONDARY OUTCOME:
Secondary end point(s): Secondary endpoints are: ; • time to cardiovascular death, myocardial infarction, or stroke, whichever occurs first ; • time to cardiovascular death ; • time to death by any cause ; • time to first myocardial infarction ; • time to first stroke ; • time to first coronary revascularization ; • time to cardiovascular death or first hospitalization for worsening heart failure, whichever occurs first ; • time to ischemic fatal or non‐fatal stroke or TIA, whichever occurs first Timepoint(s) of evaluation of this end point: •time to cardiovascular death, myocardial infarction, or stroke, whichever occurs first ; • time to cardiovascular death ; • time to death by any cause ; • time to first myocardial infarction ; • time to first stroke ; • time to first coronary revascularization ; • time to cardiovascular death or first hospitalization for worsening heart failure, whichever occurs first ; • time to ischemic fatal or non‐fatal stroke or TIA, whichever occurs first
INCLUSION CRITERIA:
4.1.1 Signed informed consent 4.1.2 Male or female = 40 to = 85 years of age at signing of informed consent 4.1.3 History of clinically evident cardiovascular disease as evidenced by ANY of the following: o diagnosis of myocardial infarction o diagnosis of non‐hemorrhagic stroke (TIA does not qualify as stroke for inclusion) o symptomatic peripheral arterial disease (PAD), as evidenced by intermittent claudication with ankle‐brachial index (ABI) < 0.85, or peripheral arterial revascularization procedure, or amputation due to atherosclerotic disease Note: the proportion of subjects with history of MI or nonhemorrhagic stroke > 5 years prior to screening will be determined by the sponsor 4.1.4 At least 1 major risk factor or at least 2 minor risk factors below: Major Risk Factors (1 Required): o diabetes (type 1 or type 2) o age = 65 years at randomization (and = 85 years at time of informed consent) o MI or non‐hem
