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Background: After acute coronary syndrome (ACS), patients with a previous myocardial infarction (MI) may be at particularly high risk for major adverse cardiovascular events (MACE) and death. We studied the effects of the PCSK9 inhibitor alirocumab in patients with recent ACS according to previous history of MI..Methods: The ODYSSEY OUTCOMES trial compared alirocumab with placebo, beginning 1 to 12 months after ACS with median 2.8-year follow-up. The primary MACE outcome comprised death from coronary heart disease, nonfatal MI, fatal or nonfatal ischemic stroke, and hospitalization for unstable angina. Of 18,924 patients, 3633 (19.2%) had previous MI. Results: Patients with previous MI were older, more likely male, with more cardiovascular risk factors and previous events. With placebo, 4-year risks of MACE and death were higher among those with vs without previous MI (20.5% vs 8.9%, P < 0.001; 7.4% vs 3.4%, P < 0.001, respectively). Alirocumab reduced the risk of events regardless of the presence or absence of a history of MI (MACE, adjusted hazard ratio [aHR] 0.90, 95% confidence interval [CI], 0.78-1.05 vs 0.82, 0.73-0.92; P-interaction = 0.34; death, aHR 0.84; 95% CI, 0.64-1.08 vs 0.87, 0.72-1.05; P-interaction = 0.81). Estimated absolute risk reductions with alirocumab were numerically greater with vs without previous MI (MACE, 1.91% vs 1.42%; death, 1.35% vs 0.41%). Conclusions: A previous history of MI places patients with recent ACS at high risk for recurrent MACE and death. Alirocumab reduced the relative risks of these events consistently in patients with or without previous MI but with numerically greater absolute benefit in the former subgroup. (ODYSSEY OUTCOMES: NCT01663402)

Elevated red blood cell distribution width (RDW) is associated with increased risk for major adverse cardiovascular events (MACE) and death in patients with cardiovascular disease. The ODYSSEY OUT-COMES trial compared alirocumab with placebo in 18,924 patients with recent acute coronary syndrome (ACS) and elevated atherogenic lipoproteins despite optimized statin treatment. This post hoc analysis determined whether RDW independently predicts risk of MACE and death in patients after recent ACS, whether RDW influences MACE reduction with alirocumab, and whether alirocumab treatment affects RDW. Associations of baseline RDW with risk of MACE and death were analyzed in the placebo group in adjusted proportional hazards models. Interactions of RDW and treatment on the risk of MACE and death were evaluated. An increasing quartile of RDW was associated with characteristics that predicted risk of MACE and death including age, hypertension, diabetes, atherosclerotic conditions and events, revascularizations, low-density lipoprotein cholesterol, and high-sensitivity C-reactive protein. After ad-justing for baseline characteristics associated with the risk of MACE or death, baseline RDW remained independently associated with the risk of MACE and death in the placebo group (hazard ratios [95% confidence intervals] 1.08 [1.02-1.15] and 1.13 [1.03-1.24] per 1% increase of RDW, respectively, both p < 0.001). There was no interaction of RDW and treatment on MACE or death, nor did alirocumab affect RDW. RDW was associated with an increased risk of MACE and death, independent of established risk factors.(c) 2022 National Lipid Association. Published by Elsevier Inc.This is an open access article under the CC BY-NC-ND license( http://creativecommons.org/licenses/by-nc-nd/4.0/ )

Aims European guidelines set low-density lipoprotein cholesterol (LDL-C) treatment goals Methods and results The ODYSSEY OUTCOMES trial (NCT01663402) compared alirocumab with placebo in 18 924 patients with recent ACS and hyperlipidaemia despite high-intensity or maximum-tolerated statin therapy. This subanalysis comprised 17 589 patients with LDL-C ≥1.4 mmol/L at baseline who did not receive ezetimibe treatment. High-intensity statin treatment was used in 88.8%. Median (interquartile range) baseline LDL-C was 2.3 (1.9−2.7) mmol/L. With alirocumab, 94.6% of patients achieved LDL-C Conclusion Among patients with recent ACS and LDL-C ≥1.4 mmol/L despite optimized statin therapy, the addition of alirocumab allowed 94.6% to achieve the 2019 European guideline LDL-C goal

Background Many patients with acute coronary syndrome have concurrent metabolic risk factors that affect risk of major adverse cardiovascular events (MACE). We aimed to assess the effects of the PCSK9 inhibitor alirocumab compared with placebo on MACE according to baseline metabolic risk factors.Methods We performed a post-hoc analysis of the ODYSSEY OUTCOMES trial, which was a multicentre, doubleblind, randomised controlled trial done in 1315 hospitals and outpatient clinics in 57 countries. Patients aged 40 years or older with recent acute coronary syndrome (ie, in the past 1-12 months) and elevated concentrations of atherogenic lipoproteins, despite high-intensity or maximum-tolerated statin treatment, were eligible for enrolment. Between Nov 2, 2012, and Feb 9,2017, patients were randomly assigned (1:1) to 75 mg alirocumab by subcutaneous injection every 2 weeks or matching placebo, beginning 1-12 months after acute coronary syndrome and were followed up for a median of 2.8 years (IQR 2.3-3.4). Patients and investigators were masked to group assignment and treatment dose adjustment. The primary outcome was a composite of death from coronary artery disease, non-fatal myocardial infarction, fatal or non-fatal ischaemic stroke, or unstable angina requiring hospital admission. Analysis of MACE according to an ordinal number of metabolic risk factors was done post hoc. Metabolic risk factors were defined as blood pressure of at least 130/85 mm Hg or treatment with antihypertensive medication, triglyceride concentration of at least 150 mg/dL, HDL cholesterol concentration less than 40 mg/dL for men and 50 mg/dL women, fasting plasma glucose concentration of at least 100 mg/dL or treatment with glucose-lowering medication, and BMI of at least 30 kg/m(2). Risk of MACE and effect of alirocumab were assessed according to the number of metabolic risk factors. ODYSSEY OUTCOMES is registered with ClinicalTrials.gov, number NCT01663402.Findings Of 18 924 patients, 3882 (41%) of 9462 in the alirocumab group and 3859 (41%) of 9462 in the placebo group had three or more metabolic risk factors. In the placebo group, MACE incidence increased monotonically with each metabolic risk factor from 7.8% (no risk factors) to 19.6% (five risk factors; HR 1.18,95% CI 1.13-1.24 per metabolic risk factor). Alirocumab decreased relative risk of MACE consistently across categories defined by the number of metabolic risk factors (p(interaction)=0.77) but absolute risk reduction (aRR) increased with the number of metabolic risk factors (no risk factors aRR 0.7%, -1.81 to 3.29 vs five risk factors aRR 3.9%, -1.45 to 9.25; p(interaction )

Aims\ud \ud Restoration of myocardial blood flow and perfusion during percutaneous coronary intervention (PCI) measured using Thrombolysis in Myocardial Infarction (TIMI) flow grade (TFG) and perfusion grade (TMPG) is associated with improved outcomes in acute coronary syndrome (ACS). Associations between TFG/TMPG and changes in biomarkers reflecting myocardial damage/dysfunction and inflammation is unknown.\ud \ud \ud \ud Methods and results\ud \ud Among 2606 patients included, TFG was evaluated in 2198 and TMPG in 1874 with ST-segment elevation myocardial infarction (STEMI) or non-ST-segment ACS (NSTE-ACS). Biomarkers reflecting myocardial necrosis [troponin T (TnT)], myocardial dysfunction [N-terminal prohormone brain natriuretic peptide (NT-proBNP)], inflammation [interleukin-6 (IL-6) and C-reactive protein (CRP)], and oxidative stress/ageing/inflammation [growth differentiation factor-15 (GDF-15)] were measured at baseline, discharge, and 1- and 6-month post-randomization. Associations between TFG/TMPG and changes in biomarker levels were evaluated using the Mann–Whitney–Wilcoxon signed test. In total, 1423 (54.6%) patients had STEMI and 1183 (45.4%) NSTE-ACS. Complete reperfusion after PCI with TFG = 3 was achieved in 1110 (85.3%) with STEMI and in 793 (88.5%) with NSTE-ACS. Normal myocardial perfusion with TMPG = 3 was achieved in 475 (41.6%) with STEMI and in 396 (54.0%) with NSTE-ACS. Levels of TnT, NT-proBNP, IL-6, CRP, and GDF-15 were substantially lower at discharge in patients with complete vs. incomplete TFG and STEMI (P < 0.01). This pattern was not observed for patients with NSTE-ACS. Patients with normal vs. abnormal TMPG and NSTE-ACS had lower levels of NT-proBNP at discharge (P = 0.01).\ud \ud \ud \ud Conclusions\ud \ud Successful restoration of epicardial blood flow in STEMI was associated with less myocardial necrosis/dysfunction and inflammation. Attainment of normal myocardial perfusion was associated with less myocardial dysfunction in NSTE-ACS.

Aims: Patients with heart failure (HF) have not been shown to benefit from statins. In a post hoc analysis, we evaluated outcomes in ODYSSEY OUTCOMES in patients with vs. without a history of HF randomized to the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor alirocumab or placebo. Methods and results: Among 18 924 patients with recent acute coronary syndrome (ACS) receiving intensive or maximum-tolerated statin treatment, the primary outcome of major adverse cardiovascular events (MACE) was compared in patients with or without a history of HF. The pre-specified secondary outcome of hospitalization for HF was also analysed. Overall, 2815 (14.9%) patients had a history of HF. Alirocumab reduced low-density lipoprotein cholesterol and lipoprotein(a) similarly in patients with or without HF. Overall, alirocumab reduced MACE compared with placebo [hazard ratio (HR): 0.85; 95% confidence interval (CI): 0.78-0.93; P = 0.0001]. This effect was observed among patients without a history of HF (HR: 0.78; 95% CI: 0.70-0.86; P < 0.0001), but not in those with a history of HF (HR: 1.17; 95% CI: 0.97-1.40; P = 0.10) (P-interaction = 0.0001). Alirocumab did not reduce hospitalization for HF, overall or in patients with or without prior HF. Conclusion: Alirocumab reduced MACE in patients without a history of HF but not in patients with a history of HF. Alirocumab did not reduce hospitalizations for HF in either group. Patients with a history of HF are a high-risk group that does not appear to benefit from PCSK9 inhibition after ACS. Key Question Patients with heart failure (HF) have not been shown to benefit from statins. In a post hoc analysis of the ODYSSEY OUTCOMES trial in patients with recent acute coronary syndrome (ACS), we evaluated major adverse cardiovascular events (MACE) in patients with or without a history of HF assigned to treatment with the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor alirocumab or placebo. Key Finding Alirocumab reduced low-density lipoprotein cholesterol similarly in patients with or without HF. However, alirocumab reduced MACE among patients without a history of HF, but not in those with a history of HF. Take Home Message The current hypothesis-generating analysis does not provide a basis to recommend PCSK9 inhibitors to patients with recent ACS and a history of HF. A prospective placebo-controlled evaluation of PCSK9 inhibition in this setting is warranted.

Background\ud \ud The efficacy of antiplatelet therapies following percutaneous coronary intervention (PCI) may be affected by body mass index (BMI).\ud \ud \ud \ud Methods and results\ud \ud This is a prespecified subgroup analysis of the GLOBAL LEADERS trial, a prospective, multicenter, open-label, randomized controlled trial in an all-comer population undergoing PCI, comparing the experimental strategy (23-month ticagrelor monotherapy following 1-month dual antiplatelet therapy [DAPT]) with a reference regimen (12-month aspirin monotherapy following 12-month DAPT). A total of 15,968 patients were stratified by baseline BMI with prespecified threshold of 27 kg/m2. Of those, 6973 (43.7%) patients with a BMI

Background\ud Trimethylamine N‐oxide (TMAO) may have prothrombotic properties. We examined the association of TMAO quartiles with major adverse cardiovascular events (MACE) and the effect of TMAO on the efficacy of ticagrelor.\ud \ud Methods and Results\ud PEGASUS‐TIMI 54 (Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin ‐ Thrombolysis in Myocardial Infarction 54) randomized patients with prior myocardial infarction to ticagrelor or placebo (median follow‐up 33 months). Baseline plasma concentrations of TMAO were measured in a nested case‐control study of 597 cases with cardiovascular death, myocardial infarction, or stroke (MACE) and 1206 controls matched for age, sex, and estimated glomerular filtration rate [eGFR]. Odds ratios (OR) were used for the association between TMAO quartiles and MACE, adjusting for baseline clinical characteristics (age, sex, eGFR, region, body mass index, hypertension, hypercholesterolemia, diabetes mellitus, smoking, peripheral artery disease, index event, aspirin dosage and treatment arm), and cardiovascular biomarkers (hs‐TnT [high‐sensitivity troponin T], hs‐CRP [high‐sensitivity C‐reactive protein], NT‐proBNP [N‐terminal‐pro‐B‐type natriuretic peptide]). Higher TMAO quartiles were associated with risk of MACE (OR for quartile 4 versus quartile 1, 1.43, 95% CI, 1.06–1.93, P trend=0.015). The association was driven by cardiovascular death (OR 2.25, 95% CI, 1.28–3.96, P trend=0.003) and stroke (OR 2.68, 95% CI, 1.39–5.17, P trend

BACKGROUND Cholesterol reduction with proprotein convertase subtitisin-kexin type 9 inhibitors reduces ischemic events; however, the cost-effectiveness in statin-treated patients with recent acute coronary syndrome remains uncertain.OBJECTIVES This study sought to determine whether further cholesterol reduction with atirocumab would be cost-effective in patients with a recent acute coronary syndrome on optimal statin therapy.METHODS A cost-effectiveness model leveraging patient-level data from ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Atirocumab) was developed to estimate costs and outcomes over a lifetime horizon. Patients (n = 18,924) had a recent acute coronary syndrome and were on high-intensity or maximum-tolerated statin therapy, with a baseline tow-density lipoprotein cholesterol (LDL-C) level >= 70 mg/l, non-high-density lipoprotein cholesterol >= 100 mg/dl, or apotipoprotein B >= 80 mg/l. Atirocumab 75 mg or placebo was administered subcutaneously every 2 weeks. Atirocumab was blindly titrated to 150 mg if LDL-C remained >= 50 mg/dl or switched to placebo if 2 consecutive LDL-C levels were = 100 mg/dl.RESULTS Across the overall population recruited to the ODYSSEY OUTCOMES trial, using an annual treatment cost of US$5,850, the mean overall incremental cost-effectiveness ratio was US$92,200 per QALY (base case). The cost was US$41,800 per QALY in patients with baseline LDL-C >= 100 mg/dl, whereas in those with LDL-C >= 100 mg/dl the cost per QALY was US$299,400. Among patients with LDL-C a100 mg/dl, incremental cost-effectiveness ratios remained below US$100,000 per QALY across a wide variety of sensitivity analyses.CONCLUSIONS In patients with a recent acute coronary syndrome on optimal statin therapy, atirocumab improves cardiovascular outcomes at costs considered intermediate value, with good value in patients with baseline LDL-C mg/dt but less economic value with LDL-C >= 100 mg/dl. (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Atirocumab [ODYSSEY OUTCOMES]; NCT01663402) (J Am Colt Cardiol 2020;75:2297-308) (C) 2020 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation.

Background: Whether the underlying risk of bleeding influences the associations between patterns of dual antiplatelet therapy (DAPT) cessation and adverse events after percutaneous coronary intervention is unknown. Methods: Patients enrolled in the prospective, international, multicenter PARIS registry (Patterns of Non-Adherence to Anti-Platelet Regimens in Stented Patients) were categorized according to their risk of bleeding using the PARIS bleeding risk score. We evaluated the incidence, patterns, and association between modes of DAPT cessation and outcomes across bleeding risk groups. Modes of DAPT cessations were defined as physician-guided DAPT discontinuation, brief interruption (

Background\ud \ud We aimed to assess associations between circulating IL‐18 concentrations and cardiovascular outcomes in patients with acute coronary syndromes (ACS).\ud \ud \ud \ud Hypothesis and Methods\ud \ud Plasma IL‐18 concentrations were measured at admission, discharge, 1 month, and 6 months in patients with ACS in the PLATelet inhibition and patient Outcomes (PLATO) trial. Associations with outcomes were evaluated with Cox regression models on the composite of CV death, spontaneous myocardial infarction (sMI), or stroke; and on CV death or sMI separately, including adjustment for clinical risk factors and biomarkers (cTnT‐hs, NT‐proBNP, cystatin C, CRP‐hs, and GDF‐15).\ud \ud \ud \ud Results\ud \ud Median IL‐18 concentrations at baseline, discharge, 1 month, and 6 months were 237, 283, 305, and 320 ng/L (n = 16 636). Male sex, obesity, diabetes, and plasma levels of cystatin C, GDF‐15, and CRP‐hs were independently associated with higher IL‐18 levels. Higher baseline IL‐18 levels were associated with the composite endpoint and with CV death (hazard ratio [HR] 1.05, 95% confidence interval [95% CI] 1.02‐1.07 and HR 1.10, 95% CI 1.06‐1.14, respectively, per 25% increase of IL‐18 levels). Associations remained significant after adjustment for clinical variables but became non‐significant after adjustment for all biomarkers (HR 1.01, 95% CI 0.98‐1.04 and HR 1.04, 95% CI 1.00‐1.08, respectively). There were no associations with sMI.\ud \ud \ud \ud Conclusions\ud \ud In ACS patients, IL‐18 concentrations increased after the acute event and remained increased for 6 months. Baseline IL‐18 levels were significantly associated with CV mortality, independent of clinical characteristics and indicators of renal/cardiac dysfunction but this association was attenuated after adjustment for multiple biomarkers.

Objectives: The aim of this study was to assess if prior oral anticoagulant agent (OAC) use modifies the lower bleeding risk observed with dabigatran dual therapy (dabigatran twice daily plus a P2Y12 inhibitor) versus warfarin triple therapy (warfarin plus a P2Y12 inhibitor plus aspirin) in patients with atrial fibrillation who underwent percutaneous coronary intervention (PCI). Background: In the RE-DUAL PCI (Randomized Evaluation of Dual Antithrombotic Therapy With Dabigatran Versus Triple Therapy With Warfarin in Patients With Nonvalvular Atrial Fibrillation Undergoing Percutaneous Coronary Intervention) trial, the primary outcome of major bleeding or clinically relevant nonmajor bleeding was lower with dabigatran dual therapy versus warfarin triple therapy in patients with atrial fibrillation who underwent PCI. Methods: A total of 2,725 patients were randomized to dual therapy with dabigatran (110 or 150 mg twice daily) plus clopidogrel or ticagrelor or triple therapy with warfarin plus aspirin and clopidogrel or ticagrelor. Subgroup analysis compared risk for major bleeding or clinically relevant nonmajor bleeding and a composite thromboembolic endpoint in patients with prior OAC use and in those who were OAC treatment naive. Results: Risk for major bleeding or clinically relevant nonmajor bleeding was reduced with both dabigatran dual therapies compared with warfarin triple therapy in both the prior OAC use group (hazard ratios: 0.58 [95% confidence interval (CI): 0.42 to 0.81] and 0.61 [95% CI: 0.41 to 0.92] with 110 and 150 mg dabigatran, respectively) and the OAC-naive group (hazard ratios: 0.49 [95% CI: 0.38 to 0.63] and 0.76 [95% CI: 0.59 to 0.97] with 110 and 150 mg dabigatran) (p for interaction = 0.42 and 0.37, 110 and 150 mg dabigatran, respectively). The risk for thromboembolic events seemed similar with dabigatran dual therapy (both doses) and warfarin triple therapy across subgroups. Conclusions: Bleeding risk was reduced with dabigatran dual therapy versus warfarin triple therapy in patients with atrial fibrillation after PCI, regardless of whether they were prior OAC users or OAC treatment naive. These results suggest that it is also safe to switch patients on OAC pre-PCI to dabigatran dual therapy post-PCI.