Effects of alirocumab on types of myocardial infarction: insights from the ODYSSEY OUTCOMES trial

Aims  The third Universal Definition of Myocardial Infarction (MI) Task Force classified MIs into five types: Type 1, spontaneous; Type 2, related to oxygen supply/demand imbalance; Type 3, fatal without ascertainment of cardiac biomarkers; Type 4, related to percutaneous coronary intervention; and Type 5, related to coronary artery bypass surgery. Low-density lipoprotein cholesterol (LDL-C) reduction with statins and proprotein convertase subtilisin–kexin Type 9 (PCSK9) inhibitors reduces risk of MI, but less is known about effects on types of MI. ODYSSEY OUTCOMES compared the PCSK9 inhibitor alirocumab with placebo in 18 924 patients with recent acute coronary syndrome (ACS) and elevated LDL-C (≥1.8 mmol/L) despite intensive statin therapy. In a pre-specified analysis, we assessed the effects of alirocumab on types of MI. Methods and results  Median follow-up was 2.8 years. Myocardial infarction types were prospectively adjudicated and classified. Of 1860 total MIs, 1223 (65.8%) were adjudicated as Type 1, 386 (20.8%) as Type 2, and 244 (13.1%) as Type 4. Few events were Type 3 (n = 2) or Type 5 (n = 5). Alirocumab reduced first MIs [hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.77–0.95; P = 0.003], with reductions in both Type 1 (HR 0.87, 95% CI 0.77–0.99; P = 0.032) and Type 2 (0.77, 0.61–0.97; P = 0.025), but not Type 4 MI. Conclusion  After ACS, alirocumab added to intensive statin therapy favourably impacted on Type 1 and 2 MIs. The data indicate for the first time that a lipid-lowering therapy can attenuate the risk of Type 2 MI. Low-density lipoprotein cholesterol reduction below levels achievable with statins is an effective preventive strategy for both MI types.For complete list of authors see http://dx.doi.org/10.1093/eurheartj/ehz299</p

Effect of alirocumab on mortality after acute coronary syndromes. An analysis of the ODYSSEY OUTCOMES randomized clinical trial

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 wit h 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

Radiation Tolerance of Nanocrystalline Ceramics: Insights from Yttria Stabilized Zirconia

Materials for applications in hostile environments, such as nuclear reactors or radioactive waste immobilization, require extremely high resistance to radiation damage, such as resistance to amorphization or volume swelling. Nanocrystalline materials have been reported to present exceptionally high radiation-tolerance to amorphization. In principle, grain boundaries that are prevalent in nanomaterials could act as sinks for point-defects, enhancing defect recombination. In this paper we present evidence for this mechanism in nanograined Yttria Stabilized Zirconia (YSZ), associated with the observation that the concentration of defects after irradiation using heavy ions (Kr(+), 400 keV) is inversely proportional to the grain size. HAADF images suggest the short migration distances in nanograined YSZ allow radiation induced interstitials to reach the grain boundaries on the irradiation time scale, leaving behind only vacancy clusters distributed within the grain. Because of the relatively low temperature of the irradiations and the fact that interstitials diffuse thermally more slowly than vacancies, this result indicates that the interstitials must reach the boundaries directly in the collision cascade, consistent with previous simulation results. Concomitant radiation-induced grain growth was observed which, as a consequence of the non-uniform implantation, caused cracking of the nano-samples induced by local stresses at the irradiated/non-irradiated interfaces

Mathematical And Physical Properties Of Reliability Models In View Of Their Application To Modern Power System Components

This chapter has a twofold purpose. The first is to present an up-to-date review of the basic theoretical and practical aspects of the main reliability models, and of some models that are rarely adopted in literature, although being useful in the authors\u2019 opinion; some very new models, or new ways to justify their adequacy, are also presented. The above aspects are illustrated from a general, meth-odological, viewpoint, but with an outlook to their application to power system component characterization, aiming at contributing to a rational model selection. Such selection should be based upon a full insight into the basic consequences of assuming \u2013 sometimes with insufficient information \u2013 a given model. The second purpose of this chapter, closely related to the first, is to highlight the rationale behind a proper and accurate selection of a reliability model for the above devices, namely a selection which is based on phenomenological and physical models of aging, i.e. on the probabilistic laws governing the process of stress and degradation acting on the device. This \u201ctechnological\u201d approach, which is also denoted in the recent literature as an \u201cindirect reliability assessment\u201d, might be in practice the only feasible in the presence of a limited amount of data, as typically occurs in the field of modern power system. Although the present contribution does not address, for reasons of brevity, the topic of model or parameter statistical estimation, the development of the indirect reliability assessment is perfectly coherent \u2013 from a \u201cphilosophical\u201d point of view \u2013 with the recent success and fast-growing adoption of the Bayesian estima-tion methodology in reliability, as proved by the ever-increasing number of papers devoted to such methodology, in particular in the field of electric and electronic engineering. In the framework of the investigation of innovations in reliability analyses regarding modern power systems, the present chapter takes its stimulus from the observation that the modern, deregulated, electrical energy market, striving towards higher system availability at lower costs, requires an accurate reliabil-ity estimation of electrical components. As witnessed by many papers appearing on the subject in literature, this is becoming an increasingly important, as well as difficult, task. This chapter gives theoretical and practical aids for the proper selection of reliability models for power system components. Firstly, the most adopted reliability models in the literature about electrical components are synthetically reviewed from the viewpoint of the classical \u201cdirect reliability assessment\u201d, i.e. a reliability assessment via statistical fitting directly from in-service failure data of components. The properties of these models, as well as their practical consequences, are discussed and it is shown that direct fitting of failure data may result poor or uncertain due to the limited number of data. Thus, practical aids for reliability assessment can be given by the knowledge of the degradation mechanisms responsible for component aging and failure. Such aging and life models, when inserted in a probabilistic framework, lead to \u201cphysical reliability models\u201d that are employed for the above-mentioned indirect reliability assessment: in this respect, a key role is played by \u201cStress-Strength\u201d models, whose properties are discussed in detail in the chapter. While the above part is essentially methodological and might be of interest even for non-electrical devices (e.g., Stress-Strength models were originally derived in mechanical engineering), very useful models can be deduced in the framework of indirect reliability assessment, that are useful both in the evaluation and at the design stage of components such as switchgears, insulators, cables, capacitors, trans-formers and rotating electrical machines. Then, since insulation is the weakest part of most electrical devices \u2013particularly in medium voltage and high voltage..