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Background: Following acute coronary syndrome (ACS), the risk for future cardiovascular events is high and is related to levels of low-density lipoprotein cholesterol (LDL-C) even within the setting of intensive statin treatment. Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates LDL receptor expression and circulating levels of LDL-C. Antibodies to PCSK9 can produce substantial and sustained reductions of LDL-C. The ODYSSEY Outcomes trial tests the hypothesis that treatment with alirocumab, a fully human monoclonal antibody to PCSK9, improves cardiovascular outcomes after ACS.
Design: This Phase 3 study will randomize approximately 18,000 patients to receive biweekly injections of alirocumab (75-150 mg) or matching placebo beginning 1 to 12 months after an index hospitalization for acute myocardial infarction or unstable angina. Qualifying patients are treated with atorvastatin 40 or 80 mg daily, rosuvastatin 20 or 40 mg daily, or the maximum tolerated and approved dose of one of these agents and fulfill one of the following criteria: LDL-C ≥ 70 mg/dL, non-high-density lipoprotein cholesterol ≥ 100 mg/dL, or apolipoprotein B ≥ 80 mg/dL. The primary efficacy measure is time to first occurrence of coronary heart disease death, acute myocardial infarction, hospitalization for unstable angina, or ischemic stroke. The trial is expected to continue until 1613 primary end point events have occurred with minimum follow-up of at least 2 years, providing 90% power to detect a 15% hazard reduction. Adverse events of special interest include allergic events and injection site reactions. Interim analyses are planned when approximately 50% and 75% of the targeted number of primary end points have occurred.
Summary: ODYSSEY Outcomes will determine whether the addition of the PCSK9 antibody alirocumab to intensive statin therapy reduces cardiovascular morbidity and mortality after ACS.
Background: Previous trials of PCSK9 (proprotein convertase subtilisin-kexin type 9) inhibitors demonstrated reductions in major adverse cardiovascular events, but not death. We assessed the effects of alirocumab on death after index acute coronary syndrome.
Methods: ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) was a double-blind, randomized comparison of alirocumab or placebo in 18 924 patients who had an ACS 1 to 12 months previously and elevated atherogenic lipoproteins despite intensive statin therapy. Alirocumab dose was blindly titrated to target achieved low-density lipoprotein cholesterol (LDL-C) between 25 and 50 mg/dL. We examined the effects of treatment on all-cause death and its components, cardiovascular and noncardiovascular death, with log-rank testing. Joint semiparametric models tested associations between nonfatal cardiovascular events and cardiovascular or noncardiovascular death.
Results: Median follow-up was 2.8 years. Death occurred in 334 (3.5%) and 392 (4.1%) patients, respectively, in the alirocumab and placebo groups (hazard ratio [HR], 0.85; 95% CI, 0.73 to 0.98; P=0.03, nominal P value). This resulted from nonsignificantly fewer cardiovascular (240 [2.5%] vs 271 [2.9%]; HR, 0.88; 95% CI, 0.74 to 1.05; P=0.15) and noncardiovascular (94 [1.0%] vs 121 [1.3%]; HR, 0.77; 95% CI, 0.59 to 1.01; P=0.06) deaths with alirocumab. In a prespecified analysis of 8242 patients eligible for ≥3 years follow-up, alirocumab reduced death (HR, 0.78; 95% CI, 0.65 to 0.94; P=0.01). Patients with nonfatal cardiovascular events were at increased risk for cardiovascular and noncardiovascular deaths (P<0.0001 for the associations). Alirocumab reduced total nonfatal cardiovascular events (P<0.001) and thereby may have attenuated the number of cardiovascular and noncardiovascular deaths. A post hoc analysis found that, compared to patients with lower LDL-C, patients with baseline LDL-C ≥100 mg/dL (2.59 mmol/L) had a greater absolute risk of death and a larger mortality benefit from alirocumab (HR, 0.71; 95% CI, 0.56 to 0.90; Pinteraction=0.007). In the alirocumab group, all-cause death declined with achieved LDL-C at 4 months of treatment, to a level of approximately 30 mg/dL (adjusted P=0.017 for linear trend).
Conclusions: Alirocumab added to intensive statin therapy has the potential to reduce death after acute coronary syndrome, particularly if treatment is maintained for ≥3 years, if baseline LDL-C is ≥100 mg/dL, or if achieved LDL-C is low.
Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01663402.
Background: Patients with acute coronary syndrome (ACS) and concomitant noncoronary atherosclerosis have a high risk of major adverse cardiovascular events (MACEs) and death. The impact of lipid lowering by proprotein convertase subtilisin–kexin type 9 inhibition in such patients is undetermined.
Objectives: This pre-specified analysis from ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) determined whether polyvascular disease influenced risks of MACEs and death and their modification by alirocumab in patients with recent ACS and dyslipidemia despite intensive statin therapy.
Methods: Patients were randomized to alirocumab or placebo 1 to 12 months after ACS. The primary MACEs endpoint was the composite of coronary heart disease death, nonfatal myocardial infarction, fatal or nonfatal ischemic stroke, or unstable angina requiring hospitalization. All-cause death was a secondary endpoint.
Results: Median follow-up was 2.8 years. Of 18,924 patients, 17,370 had monovascular (coronary) disease, 1,405 had polyvascular disease in 2 beds (coronary and peripheral artery or cerebrovascular), and 149 had polyvascular disease in 3 beds (coronary, peripheral artery, cerebrovascular). With placebo, the incidence of MACEs by respective vascular categories was 10.0%, 22.2%, and 39.7%. With alirocumab, the corresponding absolute risk reduction was 1.4% (95% confidence interval [CI]: 0.6% to 2.3%), 1.9% (95% CI: −2.4% to 6.2%), and 13.0% (95% CI: −2.0% to 28.0%). With placebo, the incidence of death by respective vascular categories was 3.5%, 10.0%, and 21.8%; the absolute risk reduction with alirocumab was 0.4% (95% CI: −0.1% to 1.0%), 1.3% (95% CI: −1.8% to 4.3%), and 16.2% (95% CI: 5.5% to 26.8%).
Conclusions: In patients with recent ACS and dyslipidemia despite intensive statin therapy, polyvascular disease is associated with high risks of MACEs and death. The large absolute reductions in those risks with alirocumab are a potential benefit for these patients. (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab [ODYSSEY OUTCOMES]: NCT01663402)
Alirocumab reduces total nonfatal cardiovascular and fatal events: The ODYSSEY OUTCOMES trial
(2018)
Background: The ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) trial compared alirocumab with placebo, added to high-intensity or maximum-tolerated statin treatment, after acute coronary syndrome (ACS) in 18,924 patients. Alirocumab reduced the first occurrence of the primary composite endpoint and was associated with fewer all-cause deaths.
Objectives: This pre-specified analysis determined the extent to which alirocumab reduced total (first and subsequent) nonfatal cardiovascular events and all-cause deaths in ODYSSEY OUTCOMES.
Methods: Hazard functions for total nonfatal cardiovascular events (myocardial infarction, stroke, ischemia-driven coronary revascularization, and hospitalization for unstable angina or heart failure) and death were jointly estimated, linked by a shared frailty accounting for patient risk heterogeneity and correlated within-patient nonfatal events. An association parameter also quantified the strength of the linkage between risk of nonfatal events and death. The model provides accurate relative estimates of nonfatal event risk if nonfatal events are associated with increased risk for death.
Results: With 3,064 first and 5,425 total events, 190 fewer first and 385 fewer total nonfatal cardiovascular events or deaths were observed with alirocumab compared with placebo. Alirocumab reduced total nonfatal cardiovascular events (hazard ratio: 0.87; 95% confidence interval: 0.82 to 0.93) and death (hazard ratio: 0.83; 95% confidence interval: 0.71 to 0.97) in the presence of a strong association between nonfatal and fatal event risk.
Conclusions: In patients with ACS, the total number of nonfatal cardiovascular events and deaths prevented with alirocumab was twice the number of first events prevented. Consequently, total event reduction is a more comprehensive metric to capture the totality of alirocumab clinical efficacy after ACS.
The production of prompt Λ+c baryons at midrapidity (|y|<0.5) was measured in central (0-10%) and mid-central (30-50%) Pb-Pb collisions at the center-of-mass energy per nucleon-nucleon pair sNN−−−√=5.02 TeV with the ALICE detector. The Λ+c production yield, the Λ+c/D0 production ratio, and the Λ+c nuclear modification factor RAA are reported. The results are more precise and more differential in transverse momentum (pT) and centrality with respect to previous measurements. The Λ+c/D0 ratio, which is enhanced with respect to the pp measurement for 4<pT<8 GeV/c, is described by theoretical calculations that model the charm-quark transport in the quark-gluon plasma and include hadronization via both coalescence and fragmentation mechanisms.
The production of J/ψ is measured as a function of charged-particle multiplicity at forward rapidity in proton-proton (pp) collisions at center-of-mass energies s√ = 5.02 and 13 TeV. The J/ψ mesons are reconstructed via their decay into dimuons in the rapidity interval (2.5 < y < 4.0), whereas the charged-particle multiplicity density (dNch/dη) is measured at midrapidity (|η| < 1). The production rate as a function of multiplicity is reported as the ratio of the yield in a given multiplicity interval to the multiplicity-integrated one. This observable shows a linear increase with charged-particle multiplicity normalized to the corresponding average value for inelastic events (dNch/dη/〈dNch/dη〉), at both the colliding energies. Measurements are compared with available ALICE results at midrapidity and theoretical model calculations. First measurement of the mean transverse momentum (〈pT〉) of J/ψ in pp collisions exhibits an increasing trend as a function of dNch/dη/〈dNch/dη〉 showing a saturation towards high charged-particle multiplicities.
The multiplicity dependence of jet production in pp collisions at the centre-of-mass energy of s√=13 TeV is studied for the first time. Jets are reconstructed from charged particles using the anti-kT algorithm with resolution parameters R varying from 0.2 to 0.7. The jets are measured in the pseudorapidity range |ηjet|<0.9−R and in the transverse momentum range 5<pchT,jet<140 GeV/c. The multiplicity intervals are categorised by the ALICE forward detector V0. The pT differential cross section of charged-particle jets are compared to leading order (LO) and next-to-leading order (NLO) perturbative quantum chromodynamics (pQCD) calculations. It is found that the data are better described by the NLO calculation, although the NLO prediction overestimates the jet cross section below 20 GeV/c. The cross section ratios for different R are also measured and compared to model calculations. These measurements provide insights into the angular dependence of jet fragmentation. The jet yield increases with increasing self-normalised charged-particle multiplicity. This increase shows only a weak dependence on jet transverse momentum and resolution parameter at the highest multiplicity. While such behaviour is qualitatively described by the present version of PYTHIA, quantitative description may require implementing new mechanisms for multi-particle production in hadronic collisions.
The energy deposited at very forward rapidities (very forward energy) is a powerful tool for characterising proton fragmentation in pp and p-Pb collisions. The correlation of very forward energy with particle production at midrapidity provides direct insights into the initial stages and the subsequent evolution of the collision. Furthermore, the correlation with the production of particles with large transverse momenta at midrapidity provides information complementary to the measurements of the underlying event, which are usually interpreted in the framework of models implementing centrality-dependent multiple parton interactions.
Results about very forward energy, measured by the ALICE zero degree calorimeters (ZDCs), and its dependence on the activity measured at midrapidity in pp collisions at s√ = 13 TeV and in p-Pb collisions at sNN−−−√ = 8.16 TeV are discussed. The measurements performed in pp collisions are compared with the expectations of three hadronic interaction event generators: PYTHIA 6 (Perugia 2011 tune), PYTHIA 8 (Monash tune), and EPOS LHC. These results provide new constraints on the validity of models in describing the beam remnants at very forward rapidities, where perturbative QCD cannot be used.
Understanding the production mechanism of light (anti)nuclei is one of the key challenges of nuclear physics and has important consequences for astrophysics, since it provides an input for indirect dark-matter searches in space. In this paper, the latest results about the production of light (anti)nuclei in pp collisions at s√ = 13 TeV are presented, focusing on the comparison with the predictions of coalescence and thermal models. For the first time, the coalescence parameters B2 for deuterons and B3 for helions are compared with parameter-free theoretical predictions that are directly constrained by the femtoscopic measurement of the source radius in the same event class. A fair description of the data with a Gaussian wave function is observed for both deuteron and helion, supporting the coalescence mechanism for the production of light (anti)nuclei in pp collisions. This method paves the way for future investigations of the internal structure of more complex nuclear clusters, including the hypertriton.
Two-particle Azimuthal correlations are measured with the ALICE apparatus in pp collisions at s√=13 TeV to explore strangeness- and multiplicity-related effects in the fragmentation of jets and the transition regime between bulk and hard production, probed with the condition that a strange meson (KS0) or baryon (Λ) with transverse momentum pT>3 GeV/c is produced. Azimuthal correlations between kaons or Λ hyperons with other hadrons are presented at midrapidity for a broad range of the trigger (3<ptriggT<20 GeV/c) and associated particle pT (1 GeV/c <passocT<ptriggT), for minimum-bias events and as a function of the event multiplicity. The near- and away-side peak yields are compared for the case of either KS0 or Λ(Λ¯¯¯¯) being the trigger particle with that of inclusive hadrons (a sample dominated by pions). In addition, the measurements are compared with predictions from PYTHIA 8 and EPOS LHC event generators.