BACKGROUND There are concerns that Asian patients respond differently to some medications. This study evaluated the efficacy and safety of evolocumab among Asian vs. other subjects in the FOURIER trial, which randomized stable atherosclerosis patients to receive either evolocumab or placebo.Methods and Results:Effects of adding evolocumab vs. placebo to background statin therapy on low-density lipoprotein cholesterol (LDL-C) reductions, cardiovascular outcomes, and adverse events were compared among 27,564 participants with atherosclerotic disease, according to self-reported Asian (n=2,723) vs. other (n=24,841) races followed for a median of 2.2 years in the FOURIER trial. The primary endpoint was a composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization. At randomization, Asians had slightly lower LDL-C (median 89 [IQR 78-104] mg/dL vs. 92 [80-109] mg/dL; P<0.001) and were much less likely to be on a high-intensity statin (33.3% vs. 73.3%; P<0.001). Evolocumab lowered LDL-C more in Asians than in others (66% vs. 58%; P<0.001). The effect of evolocumab on the primary endpoint was similar in Asians (HR, 0.79; 95% CI, 0.61-1.03) and others (HR, 0.86; 95% CI, 0.79-0.93; P interaction=0.55). There was no excess of serious adverse events with evolocumab among Asians over others. CONCLUSIONS Use of evolocumab robustly lowers LDL-C and is equally efficacious in lowering the risk of cardiovascular events and safe in Asians as it is in others.

Background: The relationship between cholesterol levels and risk of venous thromboembolism (VTE) is uncertain. We set out to determine the effect of PCSK9 inhibition on the risk of VTE, explore potential mechanisms, and examine the efficacy in clinically and genetically defined risk subgroups. Methods: We performed a post-hoc analysis of the FOURIER trial testing whether evolocumab reduces the risk of VTE events (deep venous thrombosis or pulmonary embolism). Data from FOURIER and ODYSSEY OUTCOMES were then combined in a meta-analysis to assess class effect of PCSK9 inhibition on the risk of VTE. We also analyzed baseline lipids in FOURIER to investigate potential mechanisms explaining the reduction in VTE with evolocumab. Finally, an exploratory genetic analysis was performed in FOURIER to determine whether a VTE polygenic risk score could identify high-risk patients who would derive the greatest VTE reduction from evolocumab. Results: In FOURIER, the HR for VTE with evolocumab was 0.71 (95%CI 0.50-1.00, p=0.05), with no effect in the 1st year (HR 0.96, [0.57-1.62]) but a 46% reduction (HR 0.54 [0.33-0.88], p=0.014) beyond 1 year. A meta-analysis of FOURIER and ODYSSEY OUTCOMES demonstrated a 31% relative risk reduction in VTE with PCSK9 inhibition (HR 0.69 [0.53-0.90], p=0.007). There was no relation between baseline LDL-C levels and magnitude of VTE risk reduction. In contrast, in patients with higher baseline Lp(a) levels, evolocumab reduced Lp(a) by 33 nmol/L and risk of VTE by 48% (HR 0.52 [0.30-0.89], p=0.017), whereas in patients with lower baseline Lp(a) levels evolocumab reduced Lp(a) by only 7 nmol/L and had no effect on VTE risk Pinteraction for HR 0.087, Pheterogeneity for ARR 0.037). Modeled as a continuous variable, there was a significant interaction between baseline Lp(a) concentration and magnitude of VTE risk reduction (P=0.04). A polygenic risk score identified patients who were at >2-fold increased risk for VTE and who derived greater relative (Pinteraction=0.04) and absolute VTE reduction (Pheterogeneity=0.009) compared to those without high genetic risk. Conclusions: PCSK9 inhibition significantly reduces the risk of VTE. Lp(a) reduction may be an important mediator of this effect, a finding of particular interest given ongoing development of potent Lp(a) inhibitors.

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.

Importance:Despite recent advances in treatment of severe aortic valve stenosis (AS), AS remains a life-threatening condition with no proven disease-modifying therapy. Low-density lipoprotein cholesterol (LDL-C) and lipoprotein(a) (Lp[a]) have been implicated in the pathobiology of AS. The proprotein convertase subtilisin/kexin type 9 inhibitor evolocumab reduces circulating LDL-C concentrations by 50% to 60% and Lp(a) by 20% to 30%. Objective:To determine whether evolocumab reduces the risk of AS events in patients with atherosclerotic cardiovascular disease. Interventions:Patients were randomized 1:1 to evolocumab or placebo. Design, Setting, and Participants:Exploratory analysis of the FOURIER trial, which enrolled 27 564 patients with stable atherosclerotic cardiovascular disease who were taking statin therapy at 1242 sites in 49 countries from February 2013 to November 2016. Patients were randomized to evolocumab or placebo and followed up for a median (interquartile range) of 2.2 (1.8-2.5) years. This post hoc analysis was performed from September 2019 to February 2020. Main Outcomes and Measures:Site-reported adverse events of new or worsening AS or aortic valve replacement (termed AS events). The adjusted risk of AS events was calculated with a multivariable model including concentrations of Lp(a) and LDL-C corrected for Lp(a) content, plus age, sex, diabetes, hypertension, current smoking, and estimated glomerular filtration rate. Evolocumab efficacy was tested using a Cox proportional hazards model. Results:Aortic stenosis events occurred in 63 patients (48 men [76%]; mean [SD] age, 69 [9] years) over a median of 2.2 years. Elevated Lp(a) concentration was associated with higher rates of AS events (adjusted hazard ratio [aHR], 1.55 [95% CI, 1.17-2.05] per SD; P = .002), including aortic valve replacement (aHR, 2.22 [95% CI, 1.38-3.58] per SD; P = .001), after multivariable adjustment. The corrected LDL-C concentration was not significantly associated with AS events (aHR, 1.23 [95% CI, 0.93-1.61] per SD; P = .14). The overall HR for AS events with evolocumab was 0.66 (95% CI, 0.40-1.09), with no apparent association in the first year (HR, 1.09 [95% CI, 0.48-2.47]) but an HR of 0.48 (95% CI, 0.25-0.93) after the first year of treatment. Conclusions and Relevance:In this exploratory analysis of the FOURIER trial, higher Lp(a) levels, but not Lp(a)-corrected LDL-C levels, were associated with a higher risk of subsequent AS events, including aortic valve replacement. Long-term therapy with evolocumab may reduce AS events, and this raises the possibility that specific pharmacologic lipid-lowering therapy could offer a means to prevent or slow the progression of AS. These exploratory findings merit further investigation with a dedicated randomized clinical trial. Trial Registration:ClinicalTrials.gov Identifier: NCT01764633.

Introduction: The FOURIER trial demonstrated that the PCSK9 inhibitor evolocumab robustly reduced LDL-C amongst patients on moderate or high intensity statins. We investigated whether the magnitude of the percentage LDL-C reduction is consistent across baseline LDL-C levels. Methods: FOURIER enrolled 27,564 patients with ASCVD and an LDL-C ≥70 mg/dl or a non-HDL-C ≥100 mg/dl on optimized statin therapy at the time of enrollment. The % LDL-C reduction from baseline to 12 wks was examined in patients on study drug through 12 wks (N=25,847) using a quadratic regression model including terms for treatment (evolocumab vs. placebo), baseline LDL-C and [LDL-C] 2 , and interaction terms. Stratified analyses were done for patients on high vs. moderate intensity statin. Results: Overall, compared with placebo, evolocumab reduced LDL-C by 61% (95% CI 61-62%). Patients with lower baseline LDL-C had significantly greater % LDL-C reductions (Figure top; P<0.001 for interaction between baseline LDL-C and % LDL-C reduction with evolocumab). Among patients with a baseline LDL-C of 70 mg/dL, LDL-C reduction was 68% (95% CI 67-69%) vs. 54% (95% CI 53-55%) in patients with a baseline LDL-C of 130 mg/dl. When stratified by concomitant statin intensity, similar relationships were observed (Figure middle & bottom). Conclusions: The magnitude of % LDL-C reduction with evolocumab is greater in patients with lower baseline LDL-C levels. These data are encouraging for the use of PCSK9 inhibition even for patients at the lower end of LDL-C.

Importance The PCSK9 inhibitor evolocumab reduced low-density lipoprotein cholesterol and cardiovascular events in the FOURIER randomized clinical trial. Patients with metabolic syndrome (MetS) are at increased cardiovascular risk. Objective To investigate outcomes with evolocumab in patients with and without MetS. Design, Setting, and Participants The FOURIER trial randomized patients worldwide with stable atherosclerotic cardiovascular disease receiving statin to evolocumab vs placebo with follow-up for a median of 2.2 years. Data were collected February 2013 to November 2016. For this prespecified analysis, patients with the requisite data were stratified based on the National Cholesterol Education Program Adult Treatment Panel III MetS criteria; in secondary analyses, patients were further substratified by diabetes at baseline. Analysis was intention to treat. Analysis began March 2018 and ended April 2020. Interventions Patients were randomized to evolocumab or placebo. Main Outcomes and Measures The primary end point was cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization. The key secondary end point was cardiovascular death, myocardial infarction, or stroke. Results Of 27 342 patients (mean [SD] age, 63 [9] years; 20 623 men [75.4%]) included in this analysis, 16 361 (59.8%) with baseline MetS were, when compared with patients without MetS, at higher risk of cardiovascular events (adjusted hazard ratio [95% CI], 1.31 [1.18-1.46]; P < .001 for the primary and 1.38 [1.20-1.57]; P < .001 for the key secondary end point). Evolocumab reduced low-density lipoprotein cholesterol similarly in patients with MetS (median [interquartile range], 92 [79-109] mg/dL vs 30 [19-48] mg/dL; P < .001) and without MetS (median [interquartile range], 92 [81-108] mg/dL vs 29 [18-44] mg/dl; P < .001). For the primary end point, the hazard ratios (95% CI) with evolocumab vs placebo were 0.83 (0.76-0.91) and 0.89 (0.79-1.01) in patients with and without MetS (P for interaction = .39). For the key secondary end point, the corresponding hazard ratios (95% CIs) were 0.76 (0.68-0.86) and 0.86 (0.74-1.01) (P for interaction = .23), respectively. Evolocumab did not increase the risk of new-onset diabetes or other major safety outcomes including worsening glycemic control, compared with placebo in patients with MetS. Conclusions and Relevance Patients with atherosclerotic cardiovascular disease and MetS have substantial residual risk of cardiovascular events despite statin therapy. Evolocumab significantly reduced low-density lipoprotein cholesterol and cardiovascular risk in patients with MetS without increasing new-onset diabetes, worsening glycemic control, or other major safety events. These data suggest the addition of evolocumab to statin therapy in patients with atherosclerotic cardiovascular disease and MetS is safe and efficacious to reduce residual cardiovascular risk. Trial Registration ClinicalTrials.gov Identifier: NCT01764633.

Background and Purpose— The PCSK9 (proprotein convertase subtilisin-kexin type 9) monoclonal antibody evolocumab lowered LDL (low-density lipoprotein) cholesterol by 59% to 0.8 (0.5–1.2) mmol/L and significantly reduced major vascular events in the FOURIER trial (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk). Herein, we report the results of a prespecified analysis of cerebrovascular events in the overall trial population and in patients stratified by prior stroke. Methods— FOURIER was a randomized, double-blind trial comparing evolocumab versus placebo in patients with established atherosclerosis, additional risk factors, and LDL cholesterol levels ≥1.8 (or non-HDL [high-density lipoprotein] ≥2.6 mmol/L) on statin therapy. The median follow-up was 2.2 years. We analyzed the efficacy of evolocumab to reduce overall stroke and stroke subtypes, as well as the primary cardiovascular composite end point by subgroups according to a history of stroke. Results— Among the 27 564 patients, 469 (1.7%) experienced a total of 503 strokes of which 421 (84%) were ischemic. Prior ischemic stroke, diabetes mellitus, elevated CRP (C-reactive protein), history of heart failure, older age, nonwhite race, peripheral arterial disease, and renal insufficiency were independent predictors of stroke. Evolocumab significantly reduced all stroke (1.5% versus 1.9%; hazard ratio, 0.79 [95% CI, 0.66–0.95]; P =0.01) and ischemic stroke (1.2% versus 1.6%; hazard ratio, 0.75 [95% CI, 0.62–0.92]; P =0.005), with no difference in hemorrhagic stroke (0.21% versus 0.18%; hazard ratio, 1.16 [95% CI, 0.68–1.98]; P =0.59). These findings were consistent across subgroups, including among the 5337 patients (19%) with prior ischemic stroke in whom the hazard ratios (95% CIs) were 0.85 (0.72–1.00) for the cardiovascular composite, 0.90 (0.68–1.19) for all stroke, and 0.92 (0.68–1.25) for ischemic stroke ( P interactions, 0.91, 0.22, and 0.09, respectively, compared with patients without a prior ischemic stroke). Conclusions— Inhibition of PCSK9 with evolocumab added to statin in patients with established atherosclerosis reduced ischemic stroke and cardiovascular events in the total population and in key subgroups, including those with prior ischemic stroke. Registration— URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01764633.

Introduction: Among patients with atherosclerotic cardiovascular disease (ASCVD), those with history of PCI represent an important population for potential high risk for cardiovascular (CV) events. We examined the clinical efficacy of the PCSK9 inibitor evolocumab in patients with prior PCI. Methods: FOURIER randomized 27,564 patients with ASCVD on statin therapy to evolocumab or placebo with a median follow-up of 2.2 yrs. The primary end point (PEP) was the composite of CV death, MI, stroke, unstable angina, or coronary revascularization; major coronary events were the composite of coronary death, MI, or coronary revascularization. The risk of events in patients with and without a history of PCI were compared in the placebo arm. The clinical benefit of evolocumab vs. placebo was compared using a Cox proportional hazards model. Results: 17,073 (62%) patients had prior PCI at baseline. Among patients in the placebo arm, those with prior PCI (N=8563) had a 1.6x higher rate of the PEP (16.8 vs 10.7%; adjusted HR 1.61; 95% CI 1.42-1.84 P<0.0001) and nearly double the rate of major coronary events (14.5 vs. 7.8%; P<0.0001; adjusted HR 1.72; 95% CI 1.49-1.99; Figure left). In patients with prior PCI, evolocumab reduced the risk of the PEP by 16% (HR 0.84; 95% CI 0.77-0.91; P<0.0001) and of major coronary events by 18% (HR 0.82; 95% CI 0.75-0.90, P<0.0001; Figure right), including a 30% reduction in fatal or non-fatal MI (P<0.001) and a 24% reduction in coronary revascularization (P<0.001). After the first year, there was a 25% reduction in major coronary events (HR 0.75, 95% CI 0.66-0.86, P<0.0001). The absolute risk reduction at 3 years with evolocumab for major coronary events was 2.8% in patients with prior PCI vs. 0.3% in those without. Conclusions: In a contemporary cohort with ASCVD on statin therapy, patients with prior PCI were at heightened risk for coronary events. Evolocumab was highly effective in this group, reducing major coronary events by 18% with a NNT at 3 years of only 36.

BACKGROUND The EBBINGHAUS (Evaluating PCSK9 Binding Antibody Influence on Cognitive Health in High Cardiovascular Risk Subjects) trial demonstrated that evolocumab added to a background statin did not affect cognitive performance in a subset of 1,204 patients enrolled in FOURIER (Further Cardiovascular Outcomes Research With PCSK9 inhibitors in Subjects With Elevated Risk). OBJECTIVES The authors describe patient-reported cognition in the entire FOURIER trial using a self-survey. METHODS FOURIER was a randomized, double-blind, placebo-controlled trial involving patients with atherosclerotic cardiovascular disease and low-density lipoprotein cholesterol (LDL-C) levels >= 70 mg/dl or non-high-density cholesterol >= 100 mg/dl despite statin therapy. At the final visit, patients completed a 23-item survey on memory and executive domains from the Everyday Cognition (ECog) scale. Patients compared their levels of everyday function at the end of the trial with their levels at the beginning and scored as 1 (no change or improvement), 2 (occasionally worse), 3 (consistently little worse), or 4 (consistently much worse). ECog scores were compared by the 2 randomized treatment arms and by achieved LDL-C at 4 weeks. RESULTS A total of 22,655 patients completed ECog after a median duration of 2.2 years. The proportions of patients reporting cognitive decline (ECog score >= 2) at the end of the study were similar for placebo versus evolocumab, both for total score 3.6% versus 3.7% (p = 0.62) and for subdomains (memory, 5.8% vs. 6.0%; total executive, 3.6% vs. 3.7%). The proportion of patients reporting a decline in total cognitive score was similar among the 2,338 patients who achieved very low LDL-C levels (<20 mg/dl) compared to the 3,613 patients with LDL-C >= 100 mg/dl (3.8% vs. 4.5%, p = 0.57). CONCLUSIONS The addition of evolocumab to maximally tolerated statin therapy had no impact on patient-reported cognition after an average of 2.2 years of treatment, even among patients who achieved LDL-C <20 mg/dl. (C) 2020 by the American College of Cardiology Foundation.

Background and aims: Post-acute coronary syndrome (ACS) patients are at very high risk for recurrent events and mortality, despite the availability of effective pharmacological approaches. Aim of this survey was to evaluate the compliance to ESC/EAS guidelines during the management of ACS patients and the effectiveness of secondary prevention in seven European countries. Methods: By means of an online questionnaire, data on 2775 ACS patients (either acute case or follow-up patients) were collected, including data on lipid profile, medications, follow-up visit planning, screening for familial hypercholesterolemia. Results: Lipid profiles were obtained for 91% of ACS patients in the acute phase, mostly within the first day of hospitalization (73%). During hospitalization, 93% of the patients received a lipid-lowering treatment; at discharge, only 66% of the patients received a high intensity statin therapy. At the first follow-up, most of the patients (77.6%) had LDL-C 70 mg/dL; among them, 41% had no change in their lipid-lowering therapies. Similar data were obtained during the second follow-up visit. The analysis of a subgroup of patients with at least 2 follow-up visits and known LDL-C levels showed that the percentage of patients at goal increased from 9% to 32%, and patients with LDL-C <100 mg/dL raised from 23% to 72%. Among acute cases, 44 were admitted with a diagnosis of familial hypercholesterolemia (FH); only 18% of the remaining patients were screened for FH. Conclusions: Contemporary lipid management of very high CV risk patients is sub-optimal despite available treatments. Greater efforts are warranted to optimize cardiovascular prevention. (c) 2021 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

ImportanceThe PCSK9 inhibitor evolocumab reduced major vascular events in the Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER) trial, yet the types and sizes of myocardial outcomes in FOURIER have not been previously explored.ObjectiveTo assess the types and sizes of myocardial infarction (MI) and the effect of evolocumab on MI by subtype.Design, Setting, and ParticipantsA prespecified analysis of a multicenter double-blind randomized clinical trial. Patients were randomized to evolocumab or placebo and followed up for a median of 2.2 years. The study included 27 564 patients with stable atherosclerotic disease receiving statin therapy. Clinical end points were evaluated by the Thrombolysis in Myocardial Infarction clinical events committee. Rates presented are 3-year Kaplan-Meier estimates. Data were collected from 2013 to 2016 and analyzed from June 2017 to December 2019.Main Outcomes and MeasuresMyocardial infarction was defined based on the third universal MI definition, and further classified according to MI type (universal MI subclass, ST-segment elevation myocardial infarction [STEMI] vs non-STEMI) and by MI size (determined by peak troponin level).ResultsA total of 27 564 patients were randomized, with a mean (SD) age of 62.5 (9.0) years, and 20 795 (75%) were male. Of these, 1107 patients experienced a total of 1288 MIs. Most MIs (68%) were atherothrombotic (type 1), with 15% from myocardial oxygen supply-demand mismatch (type 2) and 15% percutaneous coronary intervention-related (type 4). Sudden death (type 3) and coronary artery bypass grafting-related (type 5) accounted for a total of 21 MIs (<2%). Evolocumab significantly reduced the risk of first MI by 27% (4.4% vs 6.3%; hazard ratio [HR], 0.73; 95% CI, 0.65-0.82; P < .001), type 1 by 32% (2.9% vs 4.5%; HR, 0.68; 95% CI, 0.59-0.79; P < .001), and type 4 by 35% (0.8% vs 1.1%; HR, 0.65; 95% CI, 0.48-0.87; P = .004), with no effect on type 2 (0.9% vs 0.8%; HR, 1.09; 95% CI, 0.82-1.45; P = .56). Most MIs (688 [59.8%]) had troponin levels greater than or equal to 10 times the upper limit of normal. The benefit was highly significant and consistent regardless of the size of MI with a 34% reduction in MIs with troponin level greater than or equal to 10 times the upper limit of normal (2.6% vs 3.7%; HR, 0.66; 95% CI, 0.56-0.77; P < .001) and a 36% reduction in the risk of STEMI (1.0% vs 1.5%; HR, 0.64; 95% CI, 0.49-0.84; P < .001).Conclusions and RelevanceLow-density lipoprotein cholesterol lowering with evolocumab was highly effective in reducing the risk of MI. This reduction with evolocumab included benefit across multiple subtypes of MI related to plaque rupture, smaller and larger MIs, and both STEMI and non-STEMI. These data are consistent with the known benefit of low-density lipoprotein cholesterol lowering and underscore the reduction in clinically meaningful events.Trial RegistrationClinicalTrials.gov Identifier: NCT01764633.

Despite recent advances in treatment of severe aortic valve stenosis (AS), AS remains a common, life-threatening condition with no proven preventive therapy. Low-density lipoprotein cholesterol (LDL-C) and, particularly, lipoprotein(a) (Lp[a]) have been implicated in the pathobiology of AS. The

Introduction: Although PCSK9 inhibitors induce plaque regression and reduce the risk of coronary revascularization overall, their ability to specifically reduce the risk of complex coronary atherosclerosis requiring revascularization has not been explored. Methods: FOURIER was a randomized trial of the PCSK9 inhibitor evolocumab vs. placebo in 27,564 patients with ASCVD on statin therapy (median achieved LDL-C 32 mg/dL vs. 89 mg/dL) followed for a median of 2.2 years. The study database was blindly reviewed to assess characteristics of coronary revascularization procedures. Complex revascularization was the composite of complex PCI (per GLOBAL LEADERS criteria, at least one of: multivessel PCI, 3 or more stents implanted, 3 or more lesions treated, bifurcation PCI with 2 or more stents, or total stent length >60 mm) or CABG. PCI complications included no-reflow, side branch loss, thrombus formation, major dissection, or perforation. The effects of evolocumab on types of revascularization and PCI complications were evaluated using Cox proportional hazards models. Results: 1724 patients underwent revascularization procedures during follow-up. Evolocumab reduced the risk of non-complex PCI by 22% (HR 0.78; 95%CI 0.70-0.88; P<0.001) and the risk of complex revascularization by 29% (HR 0.71; 95%CI 0.61-0.84; P<0.001), including complex PCI by 33% (HR 0.67; 95%CI 0.54-0.84; P<0.001) and CABG by 24% (HR 0.76; 95%CI 0.60-0.96; P=0.019; Figure). The incidence of reported PCI complications tended to be lower with evolocumab (HR 0.74; 95% CI 0.49-1.11). Conclusions: Adding evolocumab to statin therapy reduced the risk of developing complex coronary disease requiring revascularization, including complex PCI and CABG individually. Together with prior coronary imaging findings, these data suggest very aggressive LDL-C lowering to <1 mmol/L has beneficial effects on coronary atherosclerosis burden, anatomical complexity, and the need for intervention.

AIMSSome trials have reported diminished efficacy for statins in the elderly, and in women compared with men. We examined the efficacy and safety of evolocumab by patient age and sex in the FOURIER trial, the first major cardiovascular outcome trial of a PCSK9 inhibitor.METHODS AND RESULTSFOURIER was a randomised, double blind trial, comparing evolocumab with placebo in 27,564 patients with atherosclerotic cardiovascular disease receiving statin therapy (median follow-up 2.2 years). The primary endpoint was cardiovascular death, myocardial infarction, stroke, hospitalisation for unstable angina or coronary revascularisation. Cox proportional hazards models were used to assess the efficacy of evolocumab versus placebo stratified by quartiles of patient age and by sex. There were small variations in the cardiovascular event rate across the age range (for the primary endpoint, Kaplan-Meier at 3 years 15.6%, >69 years, vs. 15.1%, ≤56 years, P = 0.45); however, the relative efficacy of evolocumab was consistent regardless of patient age (for the primary endpoint (Q1 hazard ratio, 95% confidence interval) 0.83, 0.72-0.96, Q2 0.88, 0.76-1.01, Q3 0.82, 0.71-0.95, Q4 0.86, 0.74-1.00; Pinteraction = 0.91), and the key secondary endpoint (cardiovascular death, myocardial infarction, stroke) (Q1 0.74 (0.61-0.89), Q2 0.83 (0.69-1.00), Q3 0.78 (0.65-0.94), Q4 0.82 (0.69-0.98)); Pinteraction = 0.81). Women had a lower primary endpoint rate than men (Kaplan-Meier at 3 years 12.5 vs. 15.3%, respectively, P < 0.001). Relative risk reductions in the primary endpoint and key secondary endpoint were similar in women (0.81 (0.69-0.95) and 0.74 (0.61-0.90), respectively) compared with men (0.86 (0.80-0.94) and 0.81 (0.73-0.90), respectively), Pinteraction = 0.48 and 0.44, respectively. Adverse events were more common in women and with increasing age but, with the exception of injection site reactions, there were no important significant differences reported by those assigned evolocumab versus placebo.CONCLUSIONSThe efficacy and safety of evolocumab are similar throughout a broad range of ages and in both men and women.