OBJECTIVE:This prespecified analysis of Effect of Evolocumab in Patients at High Cardiovascular Risk Without Prior Myocardial Infarction or Stroke (VESALIUS-CV) evaluated the efficacy of the PCSK9 inhibitor evolocumab for preventing first cardiovascular events in patients with high-risk diabetes. RESEARCH DESIGN AND METHODS:VESALIUS-CV randomized patients with high-risk diabetes (microvascular disease, insulin use, or duration ≥10 years) or qualifying atherosclerosis, but no prior myocardial infarction (MI) or stroke, and LDL cholesterol (LDL-C) ≥90 mg/dL to evolocumab 140 mg or matching placebo every 2 weeks. The dual primary end points were a composite of coronary heart disease death, MI or ischemic stroke (three-point major adverse cardiovascular event [3P-MACE]) and 3P-MACE plus ischemia-driven arterial revascularization (four-point [4P]-MACE). RESULTS:Of the 6,002 patients with high-risk diabetes, 67% were on a high-intensity statin and 24% were on a sodium-glucose cotransporter 2 inhibitor (SGLT2i) or a glucagon-like peptide 1 receptor agonist (GLP-1RA) at baseline. The median LDL-C at 48 weeks was 47 mg/dL and 109 mg/dL in the evolocumab and placebo arms, respectively (P < 0.0001). After a median follow-up of 4.6 years, evolocumab decreased the relative rates of 3P-MACE and 4P-MACE by 29% (hazard ratio [HR] 0.71; 95% CI 0.59, 0.86; P = 0.0004) and 21% (HR 0.79; 95% CI 0.69, 0.91; P = 0.0013), respectively. These findings were consistent regardless of the presence or absence of qualifying atherosclerosis, baseline LDL-C, statin intensity, and SGLT2i or GLP-1RA use (Pint > 0.05 for each). The porportion of patients with all-cause death was 8.8% vs. 11.0% in the evolocumab versus placebo arms (HR 0.79; 95% CI 0.67, 0.93). CONCLUSIONS:Evolocumab reduced the rate of cardiovascular events in patients with high-risk diabetes, regardless of the presence or absence of qualifying atherosclerosis and background use of other cardioprotective agents.

BACKGROUND:Evolocumab, a PCSK9 (proprotein convertase subtilisin-kexin type 9) inhibitor, significantly reduced the risk of cardiovascular events in patients without previous myocardial infarction or stroke in the VESALIUS-CV trial (Effect of Evolocumab in Patients at High Cardiovascular Risk without Prior Myocardial Infarction or Stroke). However, mortality results have yet to be fully characterized. METHODS:VESALIUS-CV was a double-blind study of 12 257 patients (median age, 66 years [interquartile range, 60-71]; 43% women) with qualifying atherosclerosis or high-risk diabetes without previous myocardial infarction or stroke, and low-density lipoprotein-cholesterol ≥90 mg/dL (or non-high-density lipoprotein-C ≥120 mg/dL or apolipoprotein B ≥80 mg/dL) who were randomized to evolocumab or placebo. Prespecified mortality outcomes of interest included all-cause mortality, subtypes of death (including cardiovascular [CV] and non-CV), and timing of events. Non-CV mortality was further investigated using multistate modeling to assess the contribution of prevention of nonfatal CV events (myocardial infarction, ischemic stroke, and ischemia-driven arterial revascularization) to non-CV mortality. RESULTS:Over a median of 4.6 years (interquartile range, 4.0-5.2), 973 (7.9%) patients died: 351 (36%) of CV causes, 497 (51%) of non-CV causes, and 125 (13%) of undetermined cause. All-cause mortality rates were 20% lower with evolocumab compared with placebo: 434 deaths (5-year Kaplan-Meier rate of 7.9%) with evolocumab versus 539 deaths (9.7%) with placebo (hazard ratio, 0.80, 95% CI, 0.70-0.91; P=0.0005). There was consistency of benefit for CV death (156 deaths [2.8%] versus 195 [3.6%]; hazard ratio, 0.79; 95% CI, 0.64-0.98), non-CV death (229 [4.2%] versus 268 [5.0%]; hazard ratio, 0.85; 95% CI, 0.71-1.01), and deaths of undetermined cause (49 [1.1%] versus 76 [1.4%]; hazard ratio, 0.64; 95% CI, 0.45-0.92). Results were consistent regardless of age, sex, region, race, qualifying atherosclerosis or high-risk diabetes, baseline low-density lipoprotein-cholesterol, or background lipid therapy. Postrandomization nonfatal myocardial infarction, ischemic stroke, and ischemia-driven arterial revascularization were associated with increased risk of subsequent non-CV death within the next 4 years, with the majority occurring during the first year after the event. Multistate modeling suggested the observations regarding non-CV death with evolocumab was largely (78%; bootstrap interquartile range, 71-92%) driven by the prevention of antecedent nonfatal CV events. CONCLUSIONS:These results support using evolocumab to improve survival in high-risk patients who have not experienced a previous myocardial infarction or stroke, including those with high-risk diabetes without qualifying atherosclerosis with low-density lipoprotein-cholesterol ≥ 90 mg/dl (or non-high-density lipoprotein-cholesterol ≥ 120 mg/dl or apolipoprotein B ≥ 80 mg/dl). REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT03872401.

Abstract This prespecified AZALEA-TIMI 71 analysis showed that prior oral anticoagulation (OAC) experience indicates bleeding risk in atrial fibrillation. The factor XI inhibitor abelacimab reduced bleeding regardless of prior OAC experience, with potentially greater absolute benefit among OAC-naïve patients. This trial was registered at www.ClinicalTrials.gov as NCT04755283.

BACKGROUND:Hypertriglyceridemia is associated with increased atherosclerotic cardiovascular disease and pancreatitis risk, yet durable triglyceride reduction remains challenging. Olezarsen, an antisense oligonucleotide targeting APOC3, substantially reduced triglycerides in phase 3 trials. Fibrates lower triglycerides through complementary lipoprotein lipase and apolipoprotein C-III (APOC3) pathways. Whether fibrate therapy modifies olezarsen's effects is unknown. OBJECTIVE:To evaluate the effects of olezarsen on triglycerides and other lipid parameters according to baseline fibrate use. METHODS:This prespecified secondary analysis included 3 phase 3, randomized, double-blind, placebo-controlled trials. Adults with severe hypertriglyceridemia (triglycerides ≥500 mg/dL; CORE-TIMI 72a/CORE2-TIMI 72b, pooled) or moderate hypertriglyceridemia with elevated cardiovascular risk (triglycerides 150-499 mg/dL; Essence-TIMI 73b) were randomized to monthly olezarsen (50 or 80 mg) or placebo. Placebo-adjusted triglyceride changes at 6 and 12 months were estimated using adjusted analysis-of-covariance models with treatment-by-fibrate interaction terms. Secondary endpoints included levels of APOC3 and lipid parameters, with subgroup analyses by diabetes. RESULTS:Among 1061 patients with severe and 1349 patients with moderate hypertriglyceridemia, 64% and 23% used fibrates at baseline. Olezarsen reduced triglycerides across all groups, with greater effects in fibrate users. In severe hypertriglyceridemia, placebo-adjusted triglyceride changes for fibrate users vs nonusers were -68.0% (95% CI: -75.2, -60.8) vs -53.2% (-62.9, -43.5) at 6 months (interaction P [Pint] = .02) and -66.3% (-73.4, -59.1) vs -48.4% (-58.2, -38.7) at 12 months (Pint = .004). In moderate hypertriglyceridemia, changes were -71.1% (-84.1, -58.1) vs -57.4% (-64.9, -49.9) at 6 months (Pint = .07) and -76.0% (-95.8, -56.2) vs -49.5% (-61.3, -37.8) at 12 months (Pint = .02). Similar patterns were observed for APOC3 and select atherogenic lipoproteins. Interactions were more consistently observed among patients with diabetes. Safety was similar across groups. CONCLUSION:Olezarsen reduced triglycerides across the hypertriglyceridemia spectrum, with greater effects in patients on background fibrates, particularly with diabetes. Findings support potential complementary mechanisms and further investigation of concomitant triglyceride-reducing therapy.

Aims To evaluate whether a coronary artery disease (CAD) polygenic risk score (PRS) identifies clinically low-risk individuals at elevated atherosclerotic cardiovascular disease (ASCVD) risk. Methods We conducted a longitudinal cohort study within the UK Biobank including adults aged 40–74 years, free of ASCVD and diabetes, not on lipid-lowering therapy, and with baseline LDL <190 mg/dL. Participants were enrolled from 2006 to 2010 and followed through 2021. Ten-year ASCVD risk was estimated using pooled cohort equations. A CAD PRS derived from 2.3 million genome-wide variants was categorized as top 1%, 5%, 20%, 50%, and bottom 50%. Lipoprotein(a) and high-sensitivity C-reactive protein were similarly stratified. The primary endpoint was a composite of myocardial infarction, ischemic stroke, or cardiovascular death. Cox proportional hazards models estimated adjusted hazard ratios (HRs) for 10-year ASCVD events, and net reclassification improvement (NRI) was assessed at 5% and 7.5% risk thresholds. Results Among 266,917 low-risk individuals (median age 54; 38% male), ASCVD risk increased substantially across higher PRS strata. Compared with the bottom 50%, individuals in the top 50% had more than double the risk (aHR 2.48), the top 20% had over triple the risk (aHR 3.71), and the top 5% and 1% had 6-fold (aHR 6.31) and 9-fold (aHR 9.73) higher risks, respectively (all p < 0.0001). Adding PRS improved model discrimination (AUC 0.76 vs 0.72) and reclassified 12% of low-risk individuals upward—over tenfold more than Lp(a) or hs-CRP. Conclusion In primary prevention, a CAD PRS identifies individuals with markedly higher ASCVD risk despite low clinical risk estimates and may merit consideration among ASCVD risk enhancers.

Importance:Although the Martin-Hopkins equation is widely validated and used to estimate low-density lipoprotein cholesterol (LDL-C) for clinical care, a simplified equation could streamline implementation and enable broader adoption. Objective:To develop a simplified machine learning-based alternative to the Martin-Hopkins equation using multivariate adaptive regression splines (LDL-C-MH-MARS) and compare its performance with the Friedewald (LDL-C-F), Sampson-National Institutes of Health (LDL-C-S), Modified Sampson (LDL-C-MS), and Martin-Hopkins (LDL-C-MH) equations. Design, Setting, and Participants:The Very Large Database of Lipids is a cross-sectional database of clinical lipid measurements from a population-representative convenience sample of adult and pediatric patients. Lipid measurements were performed by Vertical Auto Profile ultracentrifugation between October 1, 2015, and June 30, 2019. The study included patients with complete lipid panel data who were randomly assigned to a training set and a test set. External validation against preparative ultracentrifugation-based LDL-C measurements was performed in reference laboratory datasets from the Mayo Clinic (broad LDL-C concentrations) and the Further Cardiovascular Outcomes Research With Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibition in Subjects with Elevated Risk (FOURIER) trial (observations from patients with low LDL-C concentrations while taking evolocumab). Study data were analyzed from January to October 2025. Exposures:LDL-C-F, LDL-C-S, LDL-C-MS, LDL-C-MH, and LDL-C-MH-MARS equations. Main Outcomes and Measures:Accuracy of estimated vs ultracentrifugation-measured LDL-C concentration based on bias, root mean square error (RMSE), and concordance by guideline-based categories. Results:The study included 4 939 528 patients (mean [SD] age, 56 [16] years; 2 635 486 female [53%]) with complete lipid panel data who were randomly assigned to a training set (n = 3 292 889) and a test set (n = 1 646 639). LDL-C-MH-MARS equation demonstrated a very low median (IQR) bias of -0.1 (-2.1 to 1.8) mg/dL (to convert to millimoles per liter, multiply by 0.0259), comparable with LDL-C-MH. The median (IQR) difference between the MARS and original Martin-Hopkins equations (ie, LDL-C-MH-MARS - LDL-C-MH) was -0.5 (-1.2 to 0) mg/dL, further suggesting comparability between the 2 methods. The RMSE was smallest for LDL-C-MH-MARS (4.7 mg/dL) and LDL-C-MH (4.9 mg/dL), followed by LDL-C-S (5.8 mg/dL), LDL-C-MS (6.0 mg/dL), and LDL-C-F (7.2 mg/dL). The proportion of patients correctly classified according to clinical categories was nearly identical for LDL-C-MH-MARS (89.7%) and LDL-C-MH (89.6%) but lower for LDL-C-S (86.3%), LDL-C-MS (84.7%), and LDL-C-F (83.1%). The LDL-C-MH-MARS, LDL-C-MH, LDL-C-MS, LDL-C-S, and LDL-C-F equations underestimated LDL-C concentration in 16%, 17%, 28%, 39%, and 60%, respectively, when classifying LDL-C less than 70 mg/dL in patients with triglyceride concentrations of 200 to 399 mg/dL (to convert to millimoles per liter, multiply by 0.0113). The patterns of results were similar in external validation datasets, with the LDL-C-MH-MARS and LDL-C-MH equations demonstrating the highest accuracy. Conclusions and Relevance:Study results suggest that the new machine learning-based LDL-C equation provided results comparable with those of the original Martin-Hopkins method while simplifying implementation to a single equation.

Background Excess adiposity, most commonly indexed through body mass index (BMI), is strongly associated with the development of heart failure (HF). Weight loss therapies improve outcomes in patients with obesity and HF with preserved left ventricular ejection fraction (LVEF), but their effects in HF with reduced LVEF remain unclear. Objectives The aim of this work is to determine whether higher BMI is associated with adverse clinical outcomes in patients with HF and whether there is effect modification by LVEF subgroup. Methods Two-sample Mendelian randomization (MR) was used, with genome-wide significant loci associated with BMI as instrumental variables and outcome data from a genome-wide association study (GWAS) of time-to-event clinical outcomes in patients with HF. A total of 50,636 individuals of European ancestry with established HF from 22 cohorts were included in the genetic analysis: 12 HF trials, 1 prospective case-cohort study, 9 cohorts nested within non-HF cardiovascular trials, and 1 population-based cohort derived from the UK Biobank.The exposure was genetically predicted BMI and the outcome measures were all-cause mortality and a composite of cardiovascular mortality or HF hospitalization. Genetic associations for the outcomes were derived from our GWAS and MR was used to estimate the unbiased association of genetically predicted BMI with these clinical outcomes. Results The mean BMI was 29.2 ± 5.8 kg/m2. Over a median follow-up of 27.0 months, all-cause mortality occurred in 11,454 patients (23%), and 11,360 participants (22%) experienced the composite endpoint. Genetically predicted BMI was associated with an increased rate of both all-cause mortality (HR per SD [4.8 BMI units] 1.21; 95% CI: 1.13-1.29; P = 9 × 10-8) and the composite outcome (HR 1.29; 95% CI: 1.20-1.38; P = 8 × 10-13). Associations were consistent across LVEF ≤40% and >40%: for all-cause mortality, HR: 1.16 (95% CI: 0.99-1.37) and 1.20 (95% CI: 0.94-1.53); and for the composite outcome, HR: 1.30 (95% CI: 1.15-1.48) and 1.57 (95% CI: 1.29-1.91), respectively. Conclusions Among patients with HF, higher BMI was associated with increased all-cause mortality and cardiovascular death or HF hospitalization, supporting the potential role of weight-management strategies across the ejection fraction spectrum.

BACKGROUND AND AIMS:Lipoprotein(a) (Lp(a)) is considered a causal risk factor for atherogenesis. A higher prevalence of certain adverse events, including diabetes mellitus (DM), has been reported for patients with low Lp(a) concentrations. Therapeutics that lower Lp(a) are now in clinical testing. Thus, the association between lower Lp(a) concentration and safety outcomes is of clinical importance. METHODS:The FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) trial randomized 27 564 patients with stable atherosclerotic cardiovascular disease (ASCVD) to evolocumab versus placebo on a background of statin therapy. The relationship between Lp(a) and the risk of prevalent and incident adverse outcomes of interest was examined, adjusting for relevant predictors. RESULTS:Lp(a) was assessed in 25 090 participants at baseline (median 37 nmol/L, interquartile range 13-165). There was no association between Lp(a) concentration and incident risk of haemorrhagic stroke, serious bleeding, neurocognitive events, malignancy, or atrial fibrillation, including those with Lp(a) levels ≤13 nmol/L. There was an inverse association between lower baseline Lp(a) levels and prevalent DM at baseline (adjusted odds ratio 1.03, 95% confidence interval [CI] 1.02-1.04, P < .001; for every 50 nmol/L lower Lp(a)), as well as the incident risk of developing DM during follow-up (adjusted hazard ratio [HR] 1.05, 95% CI 1.02-1.08, P = .002; for every 50 nmol/L lower Lp(a)), with consistent results by treatment arm. Evolocumab did not increase the risk of DM irrespective of baseline Lp(a), even in participants in the top decile of baseline Lp(a) (adjusted HR .72, 95% CI .38-1.35) in whom evolocumab reduced Lp(a) by a median of 71 nmol/L. CONCLUSIONS:In patients with ASCVD, low Lp(a) concentration was not associated with an increased risk of most adverse safety outcomes, but lower Lp(a) was associated with an increased risk of prevalent and incident DM.

BACKGROUND:Whether lowering triglyceride-rich lipoproteins and remnant cholesterol favorably modifies coronary atherosclerosis is unclear. Olezarsen, an antisense oligonucleotide that targets apolipoprotein C-III, reduces triglycerides by ~60% and remnant cholesterol by ~70%, has a neutral effect on LDL (low-density lipoprotein) cholesterol (LDL-C), and reduces apoB (apolipoprotein B) by ~15% in moderate hypertriglyceridemia. We investigated the effect of olezarsen on coronary plaque in adults with largely moderate hypertriglyceridemia. METHODS:We conducted a coronary computed tomography angiography study within Essence-TIMI 73b, a randomized, placebo-controlled trial of olezarsen versus placebo that enrolled patients between November 2022 and February 2024. Inclusion criteria were triglycerides ≥150 mg/dL (2.26 mmol/L), presence of or high risk for cardiovascular disease, and, for this imaging study, noncalcified plaque on baseline coronary computed tomography angiography. The primary end point was percent change from baseline to 12 months in noncalcified plaque volume. RESULTS:Of 468 participants (349 olezarsen, 119 placebo), the median age was 63 years (interquartile range, 56-70); 31% were women, and 97% received lipid-lowering therapy. Median baseline triglycerides were 249 mg/dL (interquartile range, 197-331), and remnant cholesterol was 53 mg/dL (interquartile range, 38-76). Median baseline noncalcified plaque volume was 125.3 mm³ (interquartile range, 63.2-213.3). At 6 months, olezarsen reduced triglycerides by 63.9%, remnant cholesterol by 71.9%, and apoB by 16.0% over placebo, with no difference in LDL-C. The percent change in noncalcified plaque volume from baseline to month 12 did not differ between olezarsen and placebo (placebo-adjusted least-squares mean difference, 2.98% [95% CI, -3.4 to 9.3]; p=0.36). No significant differences between olezarsen and placebo were observed for changes in low-attenuation, calcified, or total plaque volumes at 12 months. CONCLUSIONS:Despite substantial triglyceride and remnant cholesterol lowering, treatment with olezarsen for 12 months on top of standard-of-care lipid-lowering therapy in patients with largely moderate hypertriglyceridemia did not affect noncalcified coronary plaque volume. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT05610280.

Background:Coronary CT angiography (CCTA) enables early noninvasive detection of coronary atherosclerosis, but its use in younger adults is limited by low pretest probability. Coronary artery disease polygenic risk score (CAD-PRS) may help identify individuals with increased likelihood of coronary plaque. Methods:We conducted a retrospective cohort study of patients without prior coronary artery disease who underwent CCTA between 2004 and 2021 and were genotyped through the Mass General Brigham Biobank (n = 1991), with follow-up through 2024. CAD-PRS was analyzed continuously and by risk categories (high [top decile], intermediate, low [bottom decile]). Plaque was classified as absent (CAD-RADS 0), non-obstructive (CAD-RADS 1-2), or obstructive (CAD-RADS 3-5). Extensive plaque was defined as ≥3-vessel involvement. Relative risk regression evaluated associations with plaque stratified by age. Kaplan-Meier and Cox proportional hazards models evaluated associations with adverse cardiovascular outcomes. Results:Plaque was present in 65.6% of participants, extensive plaque in 32.2%, and obstructive disease in 24.6%. Compared with the low-PRS group, high CAD-PRS was associated with greater risk of any plaque (RR 1.68, 95% CI 1.48-1.92), extensive plaque (RR 2.62, 95% CI 1.94-3.54), and obstructive disease (RR 2.82, 95% CI 1.87-4.27) (all P < .001). Associations were strongest among younger individuals (PRS-age interaction P = .017). CAD-PRS improved discrimination beyond age, sex, and traditional risk factors (C-statistic 0.832 [95% CI, 0.814-0.851] vs 0.803 [0.782-0.823]). High CAD-PRS was independently associated with increased cardiovascular events (aHR 2.76, 95% CI 1.55-4.92, P < .001). Conclusions:High CAD-PRS was independently associated with greater presence, extent, and severity of CAD on CCTA. The impact of genetic risk was strongest in younger adults-a group for whom identifying early atherosclerotic plaque may have the greatest impact.

Objective This pre-specified analysis of VESALIUS-CV evaluated the efficacy of the PCSK9i evolocumab for preventing first CV events in patients with high-risk diabetes. Research Design and Methods VESALIUS-CV randomized patients with high-risk diabetes (microvascular disease, insulin use, or duration ³10 years) or qualifying atherosclerosis, but no prior myocardial infarction (MI) or stroke, and low-density lipoprotein cholesterol (LDL-C) ≥90 mg/dL, to evolocumab 140 mg or matching placebo every 2 weeks. The dual primary endpoints were a composite of coronary heart disease death, MI or ischemic stroke (3P-MACE) and 3-P MACE plus ischemia-driven arterial revascularization (4P-MACE). Results Of the 6002 patients with high-risk diabetes, 67% were on a high-intensity statin and 24% on an SGLT2i or a GLP-1RA at baseline. The median LDL-C at 48-weeks was 47 mg/dL and 109 mg/dL in the evolocumab and placebo arms, respectively (P<0.0001). After a median follow-up of 4.6 years, evolocumab decreased 3P-MACE and 4P-MACE rates by 29% (HR 0.71; 95% CI 0.59─0.86, P=0.0004) and 21% (HR 0.79; 95% CI 0.69─0.91, P=0.0013), respectively. These findings were consistent regardless of the presence or absence of qualifying atherosclerosis, baseline LDL-C, statin intensity, and SGLT2i or GLP-1RA use (Pint >0.05 for each). The 5-year Kaplan Meier rates of all-cause death were 9.5% vs. 11.7% in the evolocumab vs. placebo arms (HR 0.79; 95% CI 0.67─0.93). Conclusions Evolocumab reduced the risk of CV events in patients with high-risk diabetes, regardless of the presence or absence of qualifying atherosclerosis and background use of other cardioprotective agents.

On the basis of seminal genetic discoveries, proprotein convertase subtilisin/kexin Type 9 (PCSK9) inhibitors were developed as a new class of LDL cholesterol-lowering drug, with a potency on par with and on top of high-intensity statins and an excellent safety profile. A series of large cardiovascular outcomes trials have now established the ability of monoclonal antibody PCSK9 inhibitors to reduce the risk of major adverse cardiovascular outcomes across a broad range of patients, including those with a prior major atherosclerotic cardiovascular disease (ASCVD) event, those with atherosclerosis but without a prior major ASCVD event, and those with diabetes. Moreover, these trials have shown the clinical benefit of lowering LDL cholesterol to ∼1 mmol/L (∼40 mg/dL) in such patients. New members of this class are being studied including oral inhibitors, RNA interference, and gene therapy.

BACKGROUND:The clinical benefit of intensive LDL cholesterol (LDL-C) lowering with evolocumab in patients with prior percutaneous coronary intervention (PCI) but without a prior myocardial infarction (MI) is not established. METHODS:VESALIUS-CV (The Effect of Evolocumabin Patients at High Cardiovascular Risk Without Prior Myocardial Infarction or Stroke) randomized patients with atherosclerosis or high-risk diabetes but without prior MI or stroke and with LDL-C ≥90 mg/dL to evolocumab versus placebo. The median follow-up was 4.6 years. The dual primary end points were coronary heart disease death, MI, or ischemic stroke (3-point major adverse cardiovascular event [MACE]) and the same composite plus ischemia-driven revascularization (4-point MACE). For this prespecified subgroup analysis, patients were categorized by whether they had undergone PCI at any time before trial enrollment. RESULTS:Among 12 257 randomized patients, 3627 (29.6%) had undergone prior PCI with a median time between PCI and enrollment of 4 years. Their median age was 66 years, and 30.7% were women. The median LDL-C in a lipid substudy at 48 weeks was 41.5 (26.0-67.0) mg/dL versus 107.0 (84.0-135.0) mg/dL in the evolocumab versus placebo arms (P<0.0001). Evolocumab reduced the relative rate of 3-point MACE by 30% (5-year Kaplan-Meier rates 7.0% versus 9.5%; hazard ratio [HR], 0.70 [95% CI, 0.56-0.89]; P=0.004) and 4-point MACE by 18% (17.9% versus 21.7%; HR, 0.82 [95% CI, 0.71-0.96]; P=0.012) as well as both MI by 50% (3.0% versus 6.1%; HR, 0.50 [95% CI, 0.36-0.70]; P<0.001), with the effect apparent as soon as 6 months after randomization, and urgent coronary revascularization by 39% (HR, 0.61 [95% CI, 0.46-0.80]; P<0.001). There were nominally lower rates of cardiovascular death (2.6% versus 3.7%; HR, 0.66 [95% CI, 0.45-0.96]; P=0.030) and all-cause death (8.2% versus 10.2%; HR, 0.76 [95% CI, 0.60-0.95]; P=0.016) with evolocumab. CONCLUSIONS:Evolocumab reduced the risk of major cardiovascular events in stable patients with prior PCI but no MI. These findings support intensive LDL-C lowering in patients who have undergone PCI even in the absence of prior MI. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT03872401.

Aims In the Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Patients with Elevated Risk (FOURIER) trial, the PCSK9 inhibitor evolocumab (Evo) significantly reduced the rate of major adverse cardiovascular events and coronary revascularization. The aim was to investigate the effect of initial randomization to Evo on the incidence of complex coronary revascularization during long-term follow-up. Methods and results In FOURIER, patients with atherosclerotic cardiovascular disease with low-density lipoprotein cholesterol (LDL-C) >= 70 mg/dL despite optimized statin therapy were randomized to Evo or placebo. At the end of the trial, patients had the option to be treated with Evo in the open-label extension (OLE) at participating sites. All cases of coronary revascularization were centrally reviewed, and complex revascularization was defined as coronary artery bypass graft surgery (CABG) or complex percutaneous coronary intervention (PCI) using the GLOBAL LEADERS definition. Event rates through 8 years were compared between patients randomized in the parent trial to Evo or placebo. Of 27 564 patients in FOURIER, 6635 patients (median achieved LDL-C 30 mg/dL) continued in OLE (total median follow-up 7.2 years). Patients initially randomized to Evo were treated on average 2.2 years earlier than patients starting treatment during OLE. In patients receiving Evo earlier, the rate for complex coronary revascularization through 8 years was reduced by 24% (HR 0.76 [0.67, 0.87], P < 0.001). This effect was consistent for both CABG (HR 0.77 [0.63, 0.94], P = 0.01) and complex PCI (HR 0.78 [0.65, 0.93], P = 0.006) individually. Early vs. delayed Evo therapy resulted in lower total stent length implanted (22 521 mm vs. 28 946 mm, P < 0.001). Conclusion Compared with delayed treatment initiation, early and sustained treatment with Evo significantly reduced the likelihood of complex revascularization during long-term follow-up. Lay summary Lowering circulating LDL-cholesterol reduces its accumulation in the blood vessels of the heart, legs, and other parts of the body, known as atherosclerosis. Evolocumab is a drug that lowers LDL-cholesterol by similar to 60%. In this study, patients with known atherosclerosis were randomly assigned to receive evolocumab earlier or later. Patients who started evolocumab earlier less frequently needed complex invasive procedures to restore the blood flow to the heart. These results show that early, aggressive lowering of LDL-cholesterol results in fewer coronary bypass surgeries and complex stenting procedures. Trial Registration clinicaltrials.gov, unique identifiers NCT01764633, NCT02867813, and NCT03080935.

BACKGROUND:Proprotein convertase subtilisin/kexin type 9 inhibition with evolocumab reduced the risk of a first major adverse cardiovascular event (MACE) in patients at high cardiovascular risk with no prior myocardial infarction (MI) or stroke in the VESALIUS-CV (Effect of Evolocumab in Patients at High Cardiovascular Risk Without Prior Myocardial Infarction or Stroke) trial. Recurrent MACE is common and important to patients, clinicians, and health care systems. OBJECTIVES:The purpose of this study was to evaluate the effect of evolocumab on total (first and subsequent) MACE. METHODS:The VESALIUS-CV trial randomized patients with qualifying atherosclerosis or high-risk diabetes, no prior MI or stroke, and a low-density lipoprotein cholesterol ≥90 mg/dL on optimized lipid-lowering therapy to evolocumab or placebo. The dual primary endpoints were a composite of coronary heart disease death, MI, ischemic stroke, or ischemia-driven arterial revascularization (4-point [4-P] MACE) and 3-point (3-P) MACE (not including ischemia-driven arterial revascularization). In this prespecified analysis, all dual primary endpoint events (first and subsequent) were analyzed using negative binomial regression models. RESULTS:Among 12,257 patients followed for a median of 4.6 years, there were 1,654 first 4-P MACE and 1,107 subsequent events (67% more) for 2,761 total events. There were 779 first 3-P MACE and 146 subsequent events (19% more) for 925 total events. Evolocumab reduced the rate of first 4-P MACE by 19% (HR: 0.81; 95% CI: 0.73-0.89; P < 0.0001), was associated with a reduction of subsequent events by 25% (incidence rate ratio [IRR]: 0.75; 95% CI: 0.61-0.91), and reduced total events by 20% (IRR: 0.80; 95% CI: 0.71-0.90; P = 0.0002). Likewise for 3-P MACE, evolocumab reduced the rate of first events by 25% (HR: 0.75; 95% CI: 0.65-0.86; P < 0.0001), was associated with a reduction of subsequent events by 37% (IRR: 0.63; 95% CI: 0.42-0.94) and reduced total events by 27% (IRR: 0.73; 95% CI: 0.63-0.86; P = 0.0001). Based on annualized incidence rate differences over the full follow-up period, evolocumab was projected to prevent 31 first and 24 subsequent 4-P MACE, for 55 total events per 1,000 patients over 5 years (95% CI: for the total-event difference: 36-74). The corresponding estimates for 3-P MACE were 20 first and 5 subsequent events, for 25 total events per 1,000 patients over 5 years (95% CI: for the total event difference: 15-37). Results were consistent across key subgroups, including by statin intensity and presence of qualifying atherosclerosis. CONCLUSIONS:A substantial proportion of patients experiencing a cardiovascular event had more than 1 event. The addition of evolocumab reduced the total number of MACE, providing support for the role of intensive low-density lipoprotein cholesterol lowering to prevent first and subsequent MACE in patients at high cardiovascular risk and no prior MI or stroke. (Effect of Evolocumab in Patients at High Cardiovascular Risk Without Prior Myocardial Infarction or Stroke [VESALIUS-CV]; NCT03872401).