Sex- and age-related differences in the management and outcomes of chronic heart failure: an analysis of patients from the ESC HFA EORP Heart Failure Long-Term Registry

Aims: This study aimed to assess age- and sex-related differences in management and 1-year risk for all-cause mortality and hospitalization in chronic heart failure (HF) patients. Methods and results: Of 16 354 patients included in the European Society of Cardiology Heart Failure Long-Term Registry, 9428 chronic HF patients were analysed [median age: 66 years; 28.5% women; mean left ventricular ejection fraction (LVEF) 37%]. Rates of use of guideline-directed medical therapy (GDMT) were high (angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, beta-blockers and mineralocorticoid receptor antagonists: 85.7%, 88.7% and 58.8%, respectively). Crude GDMT utilization rates were lower in women than in men (all differences: P\ua0 64 0.001), and GDMT use became lower with ageing in both sexes, at baseline and at 1-year follow-up. Sex was not an independent predictor of GDMT prescription; however, age >75 years was a significant predictor of GDMT underutilization. Rates of all-cause mortality were lower in women than in men (7.1% vs. 8.7%; P\ua0=\ua00.015), as were rates of all-cause hospitalization (21.9% vs. 27.3%; P\ua075 years. Conclusions: There was a decline in GDMT use with advanced age in both sexes. Sex was not an independent predictor of GDMT or adverse outcomes. However, age >75 years independently predicted lower GDMT use and higher all-cause mortality in patients with LVEF 6445%

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 hard monolithic CMOS sensors with small electrodes for High Luminosity LHC

International audienceThe upgrade of the tracking detectors for the High Luminosity-LHC (HL-LHC) requires the development of novel radiation hard silicon sensors. The development of Depleted Monolithic Active Pixel Sensors targets the replacement of hybrid pixel detectors with radiation hard monolithic CMOS sensors. We designed, manufactured and tested radiation hard monolithic CMOS sensors in the TowerJazz 180 nm CMOS imaging technology with small electrodes pixel designs. These designs can achieve pixel pitches well below current hybrid pixel sensors (typically 50 ×  50μm ) for improved spatial resolution. Monolithic sensors in our design allow to reduce multiple scattering by thinning to a total silicon thickness of only 50μm . Furthermore monolithic CMOS sensors can substantially reduce detector costs. These well-known advantages of CMOS sensor for performance and costs can only be exploited in pp-collisions at HL-LHC if the DMAPS sensors are designed to be radiation hard, capable of high hit rates and have a fast signal response to satisfy the 25 ns bunch crossing structure of LHC. Through the development of the MALTA and Mini-MALTA sensors we show the necessary steps to achieve radiation hardness at $10^{15}$  n$_{eq}$/cm$^2$ for DMAPS with small electrode designs. The sensors combine high granularity (pitch 36.4x 36.4μm$^2$), low detector capacitance (200 MHz/cm$^2$) we have implemented a novel high-speed asynchronous readout architecture. The paper summarises the optimisation of the pixel design to achieve radiation hard pixel designs with full efficiency after irradiation at > 98% after $10^{15}$  n$_{eq}$/cm$^2$)

Radiation hard monolithic CMOS sensors with small electrodes for High Luminosity LHC

The upgrade of the tracking detectors for the High Luminosity-LHC (HL-LHC) requires the development of novel radiation hard silicon sensors. The development of Depleted Monolithic Active Pixel Sensors targets the replacement of hybrid pixel detectors with radiation hard monolithic CMOS sensors. We designed, manufactured and tested radiation hard monolithic CMOS sensors in the TowerJazz 180 nm CMOS imaging technology with small electrodes pixel designs. These designs can achieve pixel pitches well below current hybrid pixel sensors (typically 50 × 50μm) for improved spatial resolution. Monolithic sensors in our design allow to reduce multiple scattering by thinning to a total silicon thickness of only 50μm. Furthermore monolithic CMOS sensors can substantially reduce detector costs. These well-known advantages of CMOS sensor for performance and costs can only be exploited in pp-collisions at HL-LHC if the DMAPS sensors are designed to be radiation hard, capable of high hit rates and have a fast signal response to satisfy the 25 ns bunch crossing structure of LHC. Through the development of the MALTA and Mini-MALTA sensors we show the necessary steps to achieve radiation hardness at 1015 neq/cm2 for DMAPS with small electrode designs. The sensors combine high granularity (pitch 36.4x36.4μm2), low detector capacitance (200 MHz/cm2) we have implemented a novel high-speed asynchronous readout architecture. The paper summarises the optimisation of the pixel design to achieve radiation hard pixel designs with full efficiency after irradiation at >98% after 1015 neq/cm2)

Radiation hard monolithic CMOS sensors with small electrodes for High Luminosity LHC

The upgrade of the tracking detectors for the High Luminosity-LHC (HL-LHC) requires the development of novel radiation hard silicon sensors. The development of Depleted Monolithic Active Pixel Sensors targets the replacement of hybrid pixel detectors with radiation hard monolithic CMOS sensors. We designed, manufactured and tested radiation hard monolithic CMOS sensors in the TowerJazz 180 nm CMOS imaging technology with small electrodes pixel designs. These designs can achieve pixel pitches well below current hybrid pixel sensors (typically 50 ×  50μm ) for improved spatial resolution. Monolithic sensors in our design allow to reduce multiple scattering by thinning to a total silicon thickness of only 50μm . Furthermore monolithic CMOS sensors can substantially reduce detector costs. These well-known advantages of CMOS sensor for performance and costs can only be exploited in pp-collisions at HL-LHC if the DMAPS sensors are designed to be radiation hard, capable of high hit rates and have a fast signal response to satisfy the 25 ns bunch crossing structure of LHC. Through the development of the MALTA and Mini-MALTA sensors we show the necessary steps to achieve radiation hardness at $10^{15}$  n$_{eq}$/cm$^2$ for DMAPS with small electrode designs. The sensors combine high granularity (pitch 36.4x 36.4μm$^2$), low detector capacitance (200 MHz/cm$^2$) we have implemented a novel high-speed asynchronous readout architecture. The paper summarises the optimisation of the pixel design to achieve radiation hard pixel designs with full efficiency after irradiation at > 98% after $10^{15}$  n$_{eq}$/cm$^2$)

Latest Developments and Results of Radiation Tolerance CMOS Sensors with Small Collection Electrodes

International audienceThis contribution will present the latest developments after the MALTA and Mini-MALTA sensors. It will illustrate the improvements and results of the Czochralski substrate with a bigger depletion zone to improve efficiency. It will also present the plans for MALTA2, which will be produced in late 2020, with enlarged transistors to reduce noise and cascoded front-end corrected slow control to improve chip operation

Mini-MALTA: Radiation hard pixel designs for small-electrode monolithic CMOS sensors for the High Luminosity LHC

Depleted Monolithic Active Pixel Sensor (DMAPS) prototypes developed in the TowerJazz 180 nm CMOS imaging process have been designed in the context of the ATLAS upgrade Phase-II at the HL-LHC. The pixel sensors are characterized by a small collection electrode (3 μm) to minimize capacitance, a small pixel size (36.4× 36.4 μm2), and are produced on high resistivity epitaxial p-type silicon. The design targets a radiation hardness of 1×1015 1 MeV neq/cm2, compatible with the outermost layer of the ATLAS ITK Pixel detector. This paper presents the results from characterization in particle beam tests of the Mini-MALTA prototype that implements a mask change or an additional implant to address the inefficiencies on the pixel edges. Results show full efficiency after a dose of 1×1015 1 MeV neq/cm2