Effect of alirocumab on coronary plaque stratified by atherothrombotic risk.

Elevated Lp(a) (lipoprotein[a]) is a risk marker for atherosclerotic disease, but the underlying mechanisms remain elusive. We examined the association of Lp(a) with changes in coronary atherosclerosis following intensive lipid-lowering therapy. In the PACMAN-AMI trial (Effects of the PCSK9 Antibody Alirocumab on Coronary Atherosclerosis in Patients With Acute Myocardial Infarction), 300 patients with acute myocardial infarction were randomized to receive biweekly alirocumab 150 mg or placebo in addition to high-intensity statins. Patients underwent serial 2-vessel intravascular ultrasound, optical coherence tomography, and near-infrared spectroscopy in the non-infarct-related arteries at baseline and after 52 weeks. The main end points were percent atheroma volume by intravascular ultrasound, minimum fibrous cap thickness by optical coherence tomography, and maximum lipid core burden index within 4 mm (maxLCBI4mm) by near-infrared spectroscopy. A total of 265 patients had serial intravascular ultrasound data (mean age, 58±9 years; 16% women). Alirocumab resulted in greater reductions in percent atheroma volume and maxLCBI4mm, as well as a greater increase in minimum fibrous cap thickness, compared with placebo. In the alirocumab group, the reduction in maxLCBI4mm was smaller in patients with higher baseline Lp(a), defined by the highest quartile (Q4, ≥98 nmol/L; n=30), than in those with lower baseline Lp(a) (Q1-Q3, <98 nmol/L; n=99; -40.2 [-91.1 to 10.7] versus -91.4 [-113.9 to -68.9], respectively; P=0.01 after adjustment for clinically relevant baseline variables), and was comparable to the maxLBI4mm reduction in the placebo group (-37.60 [-57.40 to -17.80]; n=134). These findings were consistent when higher baseline Lp(a) was defined by cut-off values of ≥75 versus <75 nmol/L (n=35 versus 94, respectively, in the alirocumab group) and ≥125 versus <125 nmol/L (n=23 versus 106, respectively). Changes in percent atheroma volume and minimum fibrous cap thickness did not differ in relation to baseline Lp(a). In patients with acute myocardial infarction, elevated Lp(a) at baseline is associated with attenuation of plaque lipid regression despite intensive treatment with alirocumab plus high-intensity statin. This finding may explain the residual cardiovascular risk associated with high Lp(a) despite optimal control of lipid levels. URL: https://www.clinicaltrials.gov; Unique identifier: NCT03067844.

SUMMARYOur observational study evaluated current management of elevated low-density lipoprotein cholesterol (LDL-C) in adult secondary prevention patients (all very high risk (VHR) by European guidelines) attending specialist clinics across Croatia. Data were collected retrospectively from patient records for the preceding 12 months. The subset judged to be at extreme risk (ER; American Association of Clinical Endocrinologists (AACE) criteria; n=48) were compared with the remaining patients (VHR group; n=41). All patients were receiving statins (75.6% VHR/81.3% ER at high-intensity), with only a minority receiving concomitant lipid-lowering treatment (7.3% VHR/16.7% ER). Median (Q1, Q3) LDL-C levels at the last visit were 1.9 (1.6, 2.4) mmol/L for VHR and 2.1 (1.5, 3.1) mmol/L for ER, with only 41.5% (95% CI 26.3-57.9) of VHR patients and 27.1% (15.3-41.9) of ER patients attaining their LDL-C targets (<1.8 mmol/L and <1.42 mmol/L, respectively). Thus, we found that a substantial proportion of VHR and ER secondary prevention patients being treated across Croatia had LDL-C levels exceeding the targets recommended in the European and newer AACE guidelines, but not all were receiving high-intensity statins. Identification of ER patients and their lipid patterns may help optimize usage of high-intensity statin treatment, alone or along with newer treatments, for better control of elevated LDL-C.

Background Patients with acute myocardial infarction (AMI) frequently experience recurrent atherothrombotic events, largely attributable to non-culprit lesions with high-risk characteristics. Statins can halt the progression of coronary atherosclerosis, and addition of protein convertase subtilisin/kexin type 9-inhibitors (PCSK9i) results in incremental low-density lipoprotein cholesterol (LDL-C) lowering and atheroma regression. Purpose We sought to examine the interrelation between baseline imaging characteristics, on-treatment LDL-C levels, and changes in coronary atherosclerosis as assessed by serial, multi-modality intracoronary imaging in patients with AMI. Methods This is a post hoc analysis from the PACMAN-AMI randomized trial. Patients were randomly allocated to biweekly alirocumab 150 mg vs. placebo on top of high-intensity statin initiated within 24h of presentation with AMI, and underwent serial imaging of the two non-infarct-related arteries at baseline and after 52 weeks. The primary endpoint was percent atheroma volume (PAV) by intravascular ultrasound (IVUS). Powered secondary endpoints were maximal lipid core burden index (maxLCBI4mm) by near-infrared spectroscopy (NIRS) and minimum fibrous cap thickness (FCTmin) by optical coherence tomography (OCT). Results Of 300 randomized patients (mean age 58.5±9.8 years, 18.7% women, baseline LDL-C 3.94±0.87 mmol/L), IVUS was serially performed in 265 patients (537 arteries). LDL-C levels decreased to 1.92±0.79 mmol/L with placebo and 0.61±0.61 mmol/L with alirocumab (p&amp;lt;0.001). Compared with placebo (statin alone), alirocumab added to statin resulted in greater PAV reduction (−2.13% vs. −0.92%; p&amp;lt;0.001), greater maxLCBI4mm reduction (−79.42 vs. −37.60; p=0.006), and greater increase in FCTmin (62.67 vs. 33.19 μm; p=0.001). Changes in PAV and maxLCBI4mm were inversely related to on-treatment LDL-C levels, and change in FCTmin was positively related to on-treatment LDL-C levels (Figure 1). Across all patients, we found significant, inverse relationships between change in PAV and baseline PAV [slope: −0.072 (95% CI −0.101 to −0.042); p&amp;lt;0.001], between change in maxLCBI4mm and baseline maxLCBI4mm [slope: −0.437 (95% CI −0.505 to −0.369); p&amp;lt;0.001], and between change in FCTmin and baseline FCTmin [slope: −0.436 (95% CI −0.541 to −0.332); p&amp;lt;0.001]; these findings indicate greater PAV and maxLCBI4mm regression in lesions with greater PAV and LCBI4mm at baseline, and greater fibrous cap thickening in lesions with thinner fibrous caps at baseline. Conclusion In this study of intensive LDL-C lowering treatment initiated in the acute AMI setting, more favorable plaque changes were observed in patients with lower on-treatment LDL-C levels and in lesions with more adverse baseline plaque characteristics. Whether AMI patients with high-risk plaque features might derive greater clinical benefit from early initiation of intensive LDL-C-lowering therapies requires further investigation. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Sanofi, Regeneron

Coronary plaques that are prone to rupture and cause adverse cardiac events are characterized by large plaque burden, large lipid content, and thin fibrous caps. Statins can halt the progression of coronary atherosclerosis; however, the effect of the proprotein convertase subtilisin kexin type 9 inhibitor alirocumab added to statin therapy on plaque burden and composition remains largely unknown. To determine the effects of alirocumab on coronary atherosclerosis using serial multimodality intracoronary imaging in patients with acute myocardial infarction. The PACMAN-AMI double-blind, placebo-controlled, randomized clinical trial (enrollment: May 9, 2017, through October 7, 2020; final follow-up: October 13, 2021) enrolled 300 patients undergoing percutaneous coronary intervention for acute myocardial infarction at 9 academic European hospitals. Patients were randomized to receive biweekly subcutaneous alirocumab (150 mg; n = 148) or placebo (n = 152), initiated less than 24 hours after urgent percutaneous coronary intervention of the culprit lesion, for 52 weeks in addition to high-intensity statin therapy (rosuvastatin, 20 mg). Intravascular ultrasonography (IVUS), near-infrared spectroscopy, and optical coherence tomography were serially performed in the 2 non-infarct-related coronary arteries at baseline and after 52 weeks. The primary efficacy end point was the change in IVUS-derived percent atheroma volume from baseline to week 52. Two powered secondary end points were changes in near-infrared spectroscopy-derived maximum lipid core burden index within 4 mm (higher values indicating greater lipid content) and optical coherence tomography-derived minimal fibrous cap thickness (smaller values indicating thin-capped, vulnerable plaques) from baseline to week 52. Among 300 randomized patients (mean [SD] age, 58.5 [9.7] years; 56 [18.7%] women; mean [SD] low-density lipoprotein cholesterol level, 152.4 [33.8] mg/dL), 265 (88.3%) underwent serial IVUS imaging in 537 arteries. At 52 weeks, mean change in percent atheroma volume was -2.13% with alirocumab vs -0.92% with placebo (difference, -1.21% [95% CI, -1.78% to -0.65%], P < .001). Mean change in maximum lipid core burden index within 4 mm was -79.42 with alirocumab vs -37.60 with placebo (difference, -41.24 [95% CI, -70.71 to -11.77]; P = .006). Mean change in minimal fibrous cap thickness was 62.67 μm with alirocumab vs 33.19 μm with placebo (difference, 29.65 μm [95% CI, 11.75-47.55]; P = .001). Adverse events occurred in 70.7% of patients treated with alirocumab vs 72.8% of patients receiving placebo. Among patients with acute myocardial infarction, the addition of subcutaneous biweekly alirocumab, compared with placebo, to high-intensity statin therapy resulted in significantly greater coronary plaque regression in non-infarct-related arteries after 52 weeks. Further research is needed to understand whether alirocumab improves clinical outcomes in this population. ClinicalTrials.gov Identifier: NCT03067844.

Objective:To compare clinical characteristics, statin treatment patterns and adherence among patients at different risk for coronary heart disease (CHD) as defined by National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III guidelines.Methods:Patients ≥18 years old with ≥1 claim for dyslipidemia, ≥1 statin claim, or ≥1 LDL-C value ≥100 mg/dL were identified from 1 January 2007 to 31 July 2012. Patients were classified as low risk (LR) (0–1 risk factor: hypertension, age ≥45 years [men] or ≥55 years [women], or low HDL-C), moderate/moderately high risk (MR) (≥2 risk factors), high risk (HR) (CHD or CHD risk equivalent), or very high risk (VHR) (acute coronary syndrome, or established cardiovascular disease plus diabetes or metabolic syndrome). Medication use and lipid levels during the 12 months before and statin use during the 6 months after index were compared across risk groups.Results:There were 1,524,351 LR, 242,357 MR, 188,222 HR, and 57,469 VHR patients identified. Statin use was observed in 15% of all patients, but was higher in the VHR group (45%) versus LR (12%), MR (18%), and HR (29%) groups. Simvastatin accounted for 50%–52% of all statin use, and average statin dose was higher among VHR patients compared with all other groups. Adherence was low overall (mean proportion of days covered [PDC]: 0.57), but higher among VHR (0.69) versus others (mean PDC: 0.55, 0.59, and 0.59 in LR, MR, and HR groups, respectively).Conclusions:Statin treatment was low across all risk groups, and VHR patients had higher doses and better adherence compared with other risk groups. However, adherence was not optimal, indicating a potential limited benefit from statin treatment.

Compared with intravascular ultrasound (IVUS), optical coherence tomography (OCT) has relative merits and demerits for detecting plaque characteristics. It remains unknown whether the IVUS and OCT evaluations of plaque progression/regression are consistent. We sought to analyse the correlations between IVUS and OCT evaluations of plaques at single time points, and compare temporal changes in the IVUS and OCT data. Eighty-eight lipid-rich plaques from 65 patients with coronary artery disease were analysed with IVUS and OCT at baseline and 12-month follow-up. Fibrous cap thickness on OCT was negatively correlated with total atheroma volume on IVUS (r = -0.28, P = 0.009), but not with percent atheroma volume (P = 0.84). Changes on OCT were not significantly correlated with changes on IVUS. Plaques that showed progression, regression, or no change on IVUS showed no differences in terms of changes in the OCT parameters fibrous cap thickness (P = 0.199), maximum lipid core arc (P = 0.755), mean lipid core arc (P = 0.936), and lipid index (P = 0.91). The incidence of thin-cap fibroatheroma (TCFA) was similar among the above three plaque groups at baseline (P = 0.79) and follow-up (P = 0.609). Although fibrous cap thickness on OCT was negatively correlated with plaque size on IVUS at single time points, changes in OCT parameters were not correlated with changes in IVUS measures over time. Lesion progression/regression on IVUS was not associated with changes in OCT parameters (fibrous cap thickness, lipid core arc, lipid index, and TCFA).

Impact of Nelarabine, Intensive L-Asparaginase, and Protracted Intrathecal Therapy on Newly Diagnosed T-Cell Acute Lymphoblastic Leukemia: Results from the Japanese Pediatric Leukemia/Lymphoma Study Group and the Japan Adult Leukemia Study Group

Are the 2015 Modifications to the National Comprehensive Cancer Network Guidelines for High-Risk and Very High-Risk Prostate Cancer Useful to Radiation Oncologists?

Background: Despite dramatic improvements in clinical outcome, intravascular ultrasound (IVUS) trials have shown minimal improvement of atheroma volume with statin therapy. Changes in plaque composition rather than plaque volume may contribute to the marked clinical benefit. Objectives: To assess the effect of intensive versus moderate lipid-lowering therapy on fibrous cap thickness (FCT) by optical coherence tomography (OCT) and percent atheroma volume (PAV) by IVUS. Methods: The patients with ≥1 non-treated lipid-rich plaque (LRP) with moderate stenosis were randomized to receive atorvastatin 60 mg (AT60), or atorvastatin 20 mg (AT20). OCT and IVUS imaging were performed at baseline, 6 months and 12 months. The primary endpoint was the change in FCT. The secondary endpoints were the change in PAV and the percent change in normalized total atheroma volume (%NTAV). Sixty-six LRP in 46 patients defined by OCT were studied. Results: Low-density lipoprotein cholesterol (LDL-C) was reduced significantly in both groups at 6 months; however, there was no further reduction at 12 months (Fig A, C). OCT demonstrated a continuous increase in FCT over time in both groups, with greater increase in the AT60 group than the AT20 group at 6 months (139.7±160.9% vs. 68.1±83.9%, p=0.021) and 12 months (211.3±125.4% vs. 120.2±136.9%, p&lt;0.0001) (Fig B, D). IVUS showed no significant changes in PAV and NTAV over time in two groups. The changes in PAV were similar between the two groups at 6 months (-0.48±3.4% in AT60 vs. 0.28±5.2% in AT20, p=0.50) and 12 months (-0.26±4.3% vs. 0.11±4.1%, p=0.73). %NTAV were also comparable between the two groups at 6 months and at 12 months. Conclusions: Intensive atorvastatin therapy induces more rapid and effective stabilization of coronary lipid-rich plaques by increasing FCT, as compared with moderate atorvastatin therapy. IVUS analysis did not show significant change in plaque volume over time in both groups.

Effects of the PCSK9 antibody alirocumab on coronary atherosclerosis in patients with acute myocardial infarction: a serial, multivessel, intravascular ultrasound, near-infrared spectroscopy and optical coherence tomography imaging study–Rationale and design of the PACMAN-AMI trial

Background Recent studies have shown that coronary artery disease regression is not limited to atheroma reduction but also includes plaque stabilization in patients treated with high-intensity lipid-lowering therapy. The frequency and characteristics of patients who simultaneously show atheroma volume reduction and plaque stabilization defined as reduction in plaque lipid content and increase in fibrous cap thickness (i.e., triple regression) are unknown. Purpose This study sought to determine the percentage and determinants of both plaque volume reduction and plaque stabilization in patients with acute myocardial infarction (MI) and treated wiTh alirocumab or placebo added to high-intensity statin therapy. Methods The PACMAN-AMI trial employed serial intravascular ultrasound, near-infrared spectroscopy and optical coherence tomography to compare the effects of alirocumab vs. placebo (1:1) in 265 patients (537 non–infarct-related coronary arteries) receiving high-intensity statin therapy. Triple regression was defined by the combined presence of reduction in percent atheroma volume (PAV), reduction in maximum lipid core burden index (maxLCBI4mm) and increase in minimal fibrous cap thickness (FCT). Clinical outcomes of patients with or without triple regression were assessed at one year follow-up. Results Overall, 199 (75.1%) patients showed PAV reduction, 180 (67.7%) maxLCBI4mm reduction and 172 (77.6%) minimal FCT increase, with a total of 84 (31.7%) patients having triple regression (40.8% in the alirocumab group vs. 23.0% in the placebo group, p=0.002). The percentage of patients with triple regression was similar among the groups with PAV reduction, maxLCBI4mm reduction or minimal FCT thickening (42%, 51% or 49%, respectively, p=0.30). Similar baseline clinical features and a higher reduction in low-density lipoprotein cholesterol (LDL-C, -27.1 [37.7 to -16.6] mg/dl, p&amp;lt;0.001) and apolipoprotein B levels (-18.5 [-26.0 to -11.0] p&amp;lt;0.001) were observed patienst with vs. without triple regression. A higher reduction in PAV (-1.54 [-2.14 to -0.95] %, p&amp;lt;0.001), maxLCBI4mm (-111.24 [-140.46 to -82.02], p&amp;lt;0.001) and a higher increase in minimal FCT (56.39 [38.67 to 74.11] µm, p&amp;lt;0.001) were found in patients with triple regression. At multivariable analysis, factors independently associated with triple regression included higher baseline maxLCBI4mm (1.03, 1.01 to 1.06, p=0.013) and alirocumab treatment (2.83, 1.57 to 5.16, p=0.001). The composite clinical endpoint of death, MI and ischemia-driven revascularization occurred less frequently in patients with versus without triple regression (8.3% vs 18.2%, p=0.042). Conclusions Triple regression occurred among one third of acute AMI patients receiving high-intensity lipid lowering therapy. Alirocumab treatment and higher baseline lipid accumulation were independent predictors of triple regression. Triple regression was associated with a reduced rate of adverse cardiovascular events.

Objective: To evaluate real-life lipid and blood pressure (BP) control in a contemporary Belgian population sample treated with at least one lipid-lowering and one antihypertensive drug. Design and method: Data was collected through GP questionnaires on 2337 subjects (ATHERO STUDY). Results: A complete set of relevant clinical variables was available for 1706 subjects (61.5% men; mean age 67.9 ± 10.9 years; mean BMI 28.4 ± 4.9 kg/m2), in which CVD, CAD, DM and renal insufficiency were reported respectively in 34.0%; 22.2%, 37.5% and 6.6% of cases. Based on the 2016 EAS/ESC guidelines for the management of dyslipidemias, 68.8% of subjects were classified as very high risk (VHR) and 10.9% as high-risk (HR). Despite the majority (almost 70%) taking &gt; 1 antihypertensive drug, BP was uncontrolled in 44.0% (using the 140/90 mmHg threshold), without clear differences in control across risk strata. Treatment targets from the 2016 LDL-cholesterol guidelines were met in only 24.4% of VHR and 45.7% of HR subjects. For the new LDL-cholesterol targets 2019 ESC/EAS guidelines for the management of dyslipidemias (which came after the data collection) this would be 10.1% and 11.7%% respectively. GP’s estimated adequate BP control in 69.2% and LDL-cholesterol control in 63.4% of cases. Combined BP and LDL-cholesterol control was achieved in 16.1% of VHR and 26.9% of HR subjects. In the VHR group there was a clear gender disparity (11.7% of women compared to 18.6% of men) in achieving adequate combined control. More striking, combined control in those VHR subjects with a clinical condition (1040/1174 subjects) was 17.9% whilst in those with VHR due to risk factor combinations this was only 2.2%. Use of combination lipid-lowering and antihypertensive drug combinations was low (1.8%) whilst 66.5% of subjects were potential candidates. Conclusions: In GP practices, target achievement was very low for BP and even more so for LDL-cholesterol prevention targets amongst VHR patients, especially in those associated to risk factor combinations rather than more easily recognizable clinical conditions. There was a clear disparity between GPs’ estimates of risk factor control/target achievement and real-life figures in GP practices.

Attainment of LDL-cholesterol target in high cardiovascular risk type 1 diabetic French people

Cranial Radiation Can be Eliminated in Most Children with T-Cell Acute Lymphoblastic Leukemia (T-ALL) and Bortezomib Potentially Improves Survival in Children with T-Cell Lymphoblastic Lymphoma (T-LL): Results of Children's Oncology Group (COG) Trial AALL1231

Objective: To evaluate the oncologic outcomes of high-risk (HR) and very high-risk (VHR) non-muscle-invasive bladder cancer (NMIBC) patients treated with Bacillus Calmette-Guérin (BCG) immunotherapy and assess the new European Association of Urology (EAU) risk stratification. Material and Methods: This retrospective cohort study analyzed data from 211 HR and VHR NMIBC patients treated with BCG therapy between January 2015 and January 2024. Risk stratification was performed using the EAU NMIBC risk calculator. Recurrence, progression, recurrence-free survival (RFS), and progression-free survival (PFS) were assessed. Results: The cohort comprised 144 (68.2%) HR and 67 (31.8%) VHR patients. The VHR group had significantly more adverse pathological features (larger and multiple tumors, higher pT stage, CIS, variant histology, lymphovascular invasion, tumor necrosis). While there was no significant difference in overall recurrence (33.3% vs. 37.3%, p=0.572) or progression rates (10.4% vs. 9%, p=0.741) between HR and VHR groups, the 5-year RFS was significantly lower in the VHR (56% vs. 75%, p=0.003). The 5-year PFS was similar between the groups (86% vs 91%, p=0.311). Conclusion: In spite of the fact that the VHR group presented with more aggressive tumor characteristics, BCG therapy resulted in similar overall progression rates compared to the HR group. These findings suggest that the EAU risk stratification may overestimate the risk of progression in BCG-treated patients, particularly those classified as VHR, and that BCG remains a valuable treatment option even in this population.