Elevated circulating lipoprotein(a) levels are associated with an increased risk of cardiovascular events. We reported that early initiation of evolocumab, a proprotein convertase subtilisin/kexin type 9 inhibitor, in addition to a statin substantially reduced the lipoprotein(a) levels in patients with acute myocardial infarction (AMI) after primary percutaneous coronary intervention (PCI). This sub-analysis sought to investigate the effect of evolocumab on lipoprotein(a) based on baseline lipoprotein(a) levels and characteristics. This study was a prespecified analysis of a randomized controlled trial that enrolled 102 patients who underwent primary PCI for AMI. Patients received pitavastatin (2 mg/day) alone or pitavastatin and evolocumab 140 mg subcutaneously within 24 h and 2 weeks after the index PCI. The evolocumab group showed significantly suppressed lipoprotein(a) levels in patients with baseline lipoprotein(a) levels of ≤10 mg/dL, 10 < lipoprotein(a) ≤ 20 mg/dL, and >20 mg/dL compared with the control group, as well as similar reductions in lipoprotein(a) levels in all patient subgroups. Among these subgroups, evolocumab tended to show more favorable effects in patients with diabetes mellitus. In AMI patients, early initiation of evolocumab therapy within 24 h of primary PCI suppressed the increase in lipoprotein(a) levels within 4 weeks, regardless of baseline levels and characteristics.

Background Evolocumab, a fully human monoclonal antibody to proprotein convertase subtilisin/kexin type 9, is safe and effective in reducing low-density lipoprotein cholesterol in adults with familial hypercholesterolemia. A dedicated study, HAUSER-RCT, is being conducted to examine the efficacy and safety of evolocumab in pediatric patients with heterozygous familial hypercholesterolemia (HeFH). Objective To present the rationale and design of the HAUSER-RCT study. Methods The HAUSER-RCT study is a double-blind, randomized, multicenter, placebo-controlled study designed to characterize the efficacy, safety, and tolerability of evolocumab treatment as an add-on to diet and lipid-lowering therapy, including a stable, optimized dose of statin, in pediatric patients aged 10 to 17 years with HeFH. Approximately, 150 patients will be randomized in a 2:1 ratio to receive 24 weeks of monthly evolocumab or placebo. The study will include approximately 51 sites located in North America, South America, Europe, South Africa, Australia, and New Zealand. The primary efficacy endpoint is the percent change in low-density lipoprotein cholesterol from baseline to week 24. A key secondary efficacy endpoint is the percent change in other lipid parameters from baseline to week 24. Other assessments include Tanner staging, carotid intima-media thickness, and cognitive tests. At the end of the study, consenting patients can participate in an 18-month open-label extension study (HAUSER-OLE). Results The study is ongoing and the results will be communicated at the end of the study. Conclusions The HAUSER-RCT study, the largest randomized, placebo-controlled study with proprotein convertase subtilisin/kexin type 9 inhibitors being conducted in the pediatric HeFH population, aims to provide efficacy, safety, and tolerability data of evolocumab as an add-on therapy in these patients. Highlights • Presenting the design and rationale of the HAUSER-RCT study. • HAUSER-RCT is a randomized ongoing study of evolocumab in children aged 10–17 years. • All participants have familial hypercholesterolemia on statin, with low-density lipoprotein cholesterol ≥130 mg/dL. • Randomization is 2:1 to blinded evolocumab or placebo for 24 weeks.

Type 2 diabetes mellitus (T2DM) is a major independent risk factor for cardiovascular disease, and diabetic dyslipidemia is a major contributor to cardiovascular risk in these patients. Here we report the rationale and design of a phase 3, double-blind study specifically designed to evaluate the lipid-lowering efficacy of the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor evolocumab in patients with T2DM and hyperlipidemia or mixed dyslipidemia who are on background statin therapy. In the BERSON (evolocumaB Efficacy for LDL-C Reduction in subjectS with T2DM On background statiN) trial, patients with T2DM, a screening low-density lipoprotein cholesterol (LDL-C) level of ≥ 2.6 mmol/L (≥100 mg/dL) or ≥ 3.4 mmol/L (≥130 mg/dL), and with or without statin treatment at screening, respectively, were enrolled and started on atorvastatin 20 mg/day for a lipid stabilization period of at least 4 weeks. Then, patients were randomly assigned in a 2:2:1:1 ratio to receive atorvastatin 20 mg once daily plus either evolocumab 140 mg every 2 weeks (Q2W), evolocumab 420 mg every month (QM), placebo Q2W, or placebo QM. The co-primary outcome measures were the percentage change from baseline in LDL-C at week 12 and the percentage change from baseline in LDL-C at the mean of weeks 10 and 12. The BERSON trial has completed enrollment. The study completed in the first half of 2018, and will provide information on the efficacy and safety of evolocumab in patients with T2DM and dyslipidemia.

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INTRODUCTION:

</b>The SECURE-PCI study supports a perioperative loading dose of statins, although whether an intensive lipid-lowering strategy prior to percutaneous coronary intervention further benefits acute coronary syndrome patients remains controversial. Evolocumab, a proprotein-converting enzyme subtilisin/kexin type 9 (PCSK9) inhibitor, acts more quickly and effectively than statins and reduces the risk of cardiovascular events in post-myocardial infarction (MI) patients. Nonetheless, whether it can be safely used in perioperative MI patients and whether perioperative application can benefit patients are still unknown. This study aims to evaluate the safety and efficacy of this treatment regimen.<b>

METHODS:

</b>A multicentre, prospective, randomized, controlled superiority trial will be conducted in 530 statin-naïve MI patients. All eligible patients will be randomized to the evolocumab group (140 mg subcutaneously injected once before revascularization + 14 days after the first dose) or the control group (no evolocumab injection). Evolocumab will then be administered depending on the patient's lipid profile. Both groups will be treated simultaneously with standardized secondary preventive medications. The primary end points are major adverse cardiovascular events (a composite of death, recurrent MI, unanticipated revascularization, stroke and any rehospitalization for ischaemic causes) within 12 months. The secondary end point is post-infarction angina after pain relief. The safety end points include myopathy, impaired liver or renal function, and other adverse events during the follow-up period.<b>Outcomes: </b>This is the first trial to evaluate the safety and efficacy of evolocumab pre-treatment on prognosis in MI patients. Perioperative evolocumab injection may be a new, safe way to improve prognosis.<b>Trial Registration: </b>Chinese Clinical Trial Registry ( http://www.chictr.org.cn ; ChiCTR1900024526). Registered on 13 July 2019 and updated on 31 May 2020. The study is currently recruiting patients.

Background: The TAUSSIG study evaluated the safety and lipid-lowering efficacy of long-term open-label evolocumab in subjects with homozygous familial hypercholesterolemia (HoFH) and severe heterozygous FH (HeFH). Interim results have been published for the HoFH cohort. Methods: Subjects with FH, aged ≥12 years and on stable lipid-lowering therapy began subcutaneous evolocumab 420 mg monthly or 420 mg every 2 weeks (Q2W) if on lipoprotein apheresis. After 12 weeks, those not on apheresis could be uptitrated to 420 mg Q2W. The primary endpoint was incidence of treatment emergent adverse events; secondary endpoints were changes in LDL-C and other lipids. Results: A total of 300 subjects (106 with HoFH, including 14 under age 18 years at enrollment) received evolocumab for a median of 4.1 years (up to 5 years). A total of 61 subjects were on apheresis. No safety signals were identified. The median change in LDL-C from baseline to week 12 was -18.3% among those with HoFH and -57.1% among those with HeFH, sustained over the course of the study (Table). Of 48 subjects who uptitrated, median change in LDL-C improved from -16.3% at week 12 to -29.3% after 12 weeks of 420 mg Q2W. Conclusion: This study, the largest and longest reported in homozygous FH, demonstrated that evolocumab was well-tolerated and effectively reduced LDL-C over a median of 4.1 years. Although relative reductions in LDL-C were smaller in subjects with HoFH, absolute reductions were similar between those with HoFH and severe HeFH. Funding: Amgen Inc. [Figure presented]

IMPORTANCE:

The 2018 American Heart Association/American College of Cardiology Multisociety Guideline on the Management of Blood Cholesterol identified patients with recent (past 12 months) myocardial infarction (MI) as very high risk, in whom a PCSK9 inhibitor is reasonable to add to maximally tolerated statin combined with ezetimibe if their low-density lipoprotein cholesterol level is 70 mg/dL or greater or non-high-density lipoprotein cholesterol level is 100 mg/dL or greater.

OBJECTIVE:

To examine the clinical efficacy of evolocumab in patients with recent MI.

DESIGN, SETTING, AND PARTICIPANTS:

This was a prespecified secondary analysis of the Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER) trial, in which 27 564 patients with atherosclerotic cardiovascular disease treated with a statin were randomized to evolocumab vs placebo. Patients with prior MI with a known date (n = 22 320) were stratified as having a recent MI (within 12 months of randomization) or a remote MI (more than 12 months prior to randomization). Per protocol, patients with MI within 4 weeks prior to randomization were excluded from the FOURIER trial. Data were collected from February 2013 to November 2016, and data were analyzed from May 2019 to February 2020.

MAIN OUTCOMES AND MEASURES:

The primary composite end point was cardiovascular death, MI, stroke, hospitalization for unstable angina, or coronary revascularization. The key secondary composite end point was cardiovascular death, MI, or stroke.

RESULTS:

Of 22 320 included patients, 17 516 (78.5%) were male, and the mean (SD) age was 62.2 (9.0) years. Compared with 16 609 patients with a remote MI, 5711 patients with a recent MI were younger and more likely to be treated with high-intensity statin (77.3% [4415] vs 69.3% [11 506]). In the placebo arm, the 3-year Kaplan-Meier rate for the primary end point was 17.2% in patients with recent MI compared with 14.4% in those with remote MI (adjusted HR, 1.45; 95% CI, 1.29-1.64; P < .001). Similarly, the 3-year Kaplan-Meier rates for the key secondary end point was also higher in those with recent MI (10.9% vs 9.5%; adjusted HR, 1.45; 95% CI, 1.24-1.69; P < .001). In patients with a recent MI, evolocumab reduced the risk of the primary and key secondary end points by 19% (hazard ratio [HR], 0.81; 95% CI, 0.70-0.93) and 25% (HR, 0.75; 95% CI, 0.62-0.91), respectively. In patients with a remote MI, evolocumab reduced the risk of the primary and key secondary end points by 8% (HR, 0.92; 95% CI, 0.84-1.01; P for interaction = .13) and 15% (HR, 0.85; 95% CI, 0.76-0.96; P for interaction = .24), respectively. Given the higher event rates in patients with a recent MI, the absolute risk reductions over 3 years with evolocumab were 3.7% in those with recent MI vs 1.1% in those with remote MI for the primary end point and 3.2% vs 1.3%, respectively, for the key secondary end point.

CONCLUSIONS AND RELEVANCE:

Patients with a recent MI were at higher risk of cardiovascular events and tended to experience greater absolute risk reductions with evolocumab than those with remote MIs. These findings support the concept in US and European guidelines to aggressively lower low-density lipoprotein cholesterol levels in very high-risk patients, such as those with a recent MI.

TRIAL REGISTRATION:

ClinicalTrials.gov Identifier: NCT01764633.

OBJECTIVE:

To evaluate the clinical efficacy of intensive LDL cholesterol (LDL-C) lowering in type 1 diabetes mellitus (T1DM).

RESEARCH DESIGN AND METHODS:

Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER) randomized participants with atherosclerotic cardiovascular disease (ASCVD) on statins to evolocumab or placebo (median follow-up 2.2 years). The primary end point (PEP) was cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization.

RESULTS:

Of 27,564 participants, 10,834 (39.3%) had type 2 diabetes mellitus (T2DM), and 197 (0.7%) had T1DM. In the placebo arm, there was a stepwise increase in the 2.5-year PEP Kaplan-Meier rate from 11.0% to 15.2% to 20.4% in participants with no diabetes, T2DM, and T1DM, respectively (P < 0.0001). Hazard ratios for PEP with evolocumab were 0.87 (95% CI 0.79-0.96), 0.84 (0.75-0.93), and 0.66 (0.32-1.38) in the no diabetes, T2DM, and T1DM groups, and absolute risk reduction was 1.3%, 2.5%, and 7.3%, respectively.

CONCLUSIONS:

Intensive LDL-C lowering may provide substantial clinical benefit in individuals with T1DM and ASCVD. Additional randomized controlled cardiovascular outcomes trials are needed in this population.

INTERVENTION:

Product Name: Repatha Pharmaceutical Form: Solution for injection in pre‐filled injector Pharmaceutical form of the placebo: Solution for injection in pre‐filled injector Route of administration of the placebo: Subcutaneous use

CONDITION:

Patency of graft after coronary bypass graft surgery in patients with hyprelipidaemia ; MedDRA version: 20.0 Level: LLT Classification code 10011079 Term: Coronary artery disease NOS System Organ Class: 100000004849 Therapeutic area: Diseases [C] ‐ Cardiovascular Diseases [C14]

PRIMARY OUTCOME:

Main Objective: Given that graft failure is associated with increased morbidity and mortality, and that lipid lowering interventions may reduce vein graft occlusion, the objectives of this study are to determine if intensive LDL‐cholesterol lowering with evolocumab will result in improved vein graft patency compared to placebo following CABG surgery. Primary end point(s): The primary endpoint of the study is the saphenous vein graft disease rate (VGDR) defined as the proportion of vein grafts with significant stenosis or total occlusion (=50%) on 64‐slice (or greater) cardiac CT angiography (CTA) or clinically indicated coronary angiography 24 months post CABG.; Secondary Objective: None Timepoint(s) of evaluation of this end point: At the end of 24th month

SECONDARY OUTCOME:

Secondary end point(s): • The proportion of patients with at least 1 vein graft totally (100%) occluded at 24 months; • The percentage of vein grafts which are totally occluded (100%) grafts at 24 months; Timepoint(s) of evaluation of this end point: At the end of 24th month

INCLUSION CRITERIA:

To be considered eligible for participation in this study, a participant must satisfy each of the following criteria: 1. Age = 18 years 2. Scheduled to undergo coronary artery bypass graft (CABG) surgery (with or without cardiopulmonary bypass (CPB); with or without single valve repair/replacement) 3. CABG procedure included/planned to include at least two saphenous vein grafts 4. CABG procedure occurred within the past 21 days, or is planned within the next 60 days 5. On a moderate to high intensity statin therapy (defined as atorvastatin 40‐80 mg daily, rosuvastatin 20‐40 mg, or simvastatin 40 mg daily) unless a lower dose, or another statin or non‐statin therapy is clinically justified Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18‐64 years) yes F.1.2.1 Number of subjects for this age range 300 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 466

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Aim: To examine the lipid and glycaemic effects of 52 weeks of treatment with evolocumab. Materials and Methods: The Durable Effect of PCSK9 Antibody Compared with Placebo Study (DESCARTES) was a 52-week placebo-controlled trial of evolocumab that randomized 905 patients from 88 study centres in 9 countries, with 901 receiving at least one dose of study drug. For this post-hoc analysis, DESCARTES patients were categorized by baseline glycaemic status: type 2 diabetes, impaired fasting glucose (IFG), metabolic syndrome (MetS) or none of these. Monthly subcutaneous evolocumab (420 mg) or placebo was administered. The main outcomes measured were percentage change in LDL-cholesterol (LDL-C) at week 52 and safety. Results: A total of 413 patients had dysglycaemia (120, type 2 diabetes; 293, IFG), 289 had MetS (194 also had IFG) and 393 had none of these conditions. At week 52, evolocumab reduced LDL-C by >50% in all subgroups, with favourable effects on other lipids. No significant differences in fasting plasma glucose, HbA1c, insulin, C-peptide or HOMA indices were seen in any subgroup between evolocumab and placebo at week 52. The overall incidence of new-onset diabetes mellitus did not differ between placebo (6.6%) and evolocumab (5.6%); in those with baseline normoglycaemia, the incidences were 1.9% and 2.7%, respectively. Incidences of AEs were similar in evolocumab- and placebo-treated patients. Conclusions: Evolocumab showed encouraging safety and efficacy at 52 weeks in patients with or without dysglycaemia or MetS. Changes in glycaemic parameters did not differ between evolocumab- and placebo-treated patients within the glycaemic subgroups examined. © 2016 John Wiley & Sons Ltd