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This secondary analysis of findings from a trial that assessed the effect of low-density lipoprotein cholesterol levels in patients with coronary artery disease shows that body-weight fluctuation was associated with an increased risk of death and cardiovascular events. Obesity is an independent risk factor for cardiovascular death and disease. 1 , 2 Among participants in the Framingham Heart Study who were between 35 and 75 years of age and were followed for up to 44 years, overweight and obese participants were at a higher risk for the development of cardiovascular disease than participants of normal weight. 3 Weight gain is strongly associated with an increased risk of death and disease among participants without evident cardiovascular disease at baseline. 4 , 5 Indeed, in obese persons, bariatric surgery followed by weight loss reduces the risk of cardiovascular disease, including hypertension, hypercholesterolemia, and diabetes. 6 – . . .

In patients with previous myocardial infarction (MI), aggressive hypertension control and low-density lipoprotein cholesterol (LDL-C) reduction are important secondary prevention measures. However, residual risk remains despite aggressive treatment. Whether variability in blood pressure (BP) and LDL-C can explain this residual risk is not known. Patients enrolled in the Incremental Decrease in End Points Through Aggressive Lipid-Lowering trial with at least 1 post-baseline measurement of LDL-C and blood pressure (BP) were included. Visit-to-visit LDL-C and BP variabilities were evaluated using various measures of variability. Primary outcome was any coronary event with the secondary outcomes of any cardiovascular event (CV), MI, stroke, death, and CV death. Among the 8,658 patients included, each 1-SD (10.8 mg/dl) increase in LDL-C variability increased the risk of any coronary event (adjusted HR [HRadj] 1.07; 95% CI 1.04 to 1.11; p <0.0001), any CV event, MI, and death (HRadj 1.19; 95% CI 1.14 to 1.25; p <0.0001). Similarly, each 1-SD (7.2 mm Hg) increase in systolic BP variability increased the risk of any coronary event (HRadj 1.15; 95% CI 1.10 to 1.20; p <0.0001), any CV event, MI, stroke, death (HRadj 1.28; 95% CI 1.18 to 1.38; p <0.0001), and CV death. Compared with the group with low variability for both LDL-C and systolic BP, the group with high variability for both had a significant increase in any coronary event (HRadj 1.48; 95% CI 1.30 to 1.70), any CV event (HRadj 1.43; 95% CI 1.27 to 1.61), and MI (HRadj 1.87; 95% CI 1.46 to 2.41). In conclusions, in patients with a history of MI, variabilities in LDL-C and BP are powerful and independent predictors of CV events including death.

The aim of this study was to evaluate the effect of atorvastatin on lipid lowering, cardiovascular (CV) events, and adverse events in women compared with men in 6 clinical trials. In the Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) trial (atorvastatin 80 mg vs simvastatin 20 to 40 mg), the Treating to New Targets (TNT) trial (atorvastatin 80 vs 10 mg), the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial (atorvastatin 80 mg vs placebo), and the Collaborative Atorvastatin Diabetes Study (CARDS), the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), and the Atorvastatin Study for Prevention of Coronary Heart Disease Endpoints in Non-Insulin-Dependent Diabetes Mellitus (ASPEN) (atorvastatin 10 mg vs placebo), lipid changes on treatment were compared between genders with studies grouped by dose. The association of on-study low-density lipoprotein (LDL) cholesterol and CV events by gender was evaluated in the combined studies and the impact of gender on adverse events in each study separately. Major CV events occurred in 3,083 of 30,000 men (10.3%) and 823 of 9,173 women (9.0%). Changes in lipids were similar in women and men. Major CV events were associated with gender-specific quintiles of on-treatment LDL cholesterol for women and men. In women, LDL cholesterol was a significant predictor of stroke, but not in men. Discontinuation rates due to adverse events were higher in women in 4 of 6 trials, but in only 1 trial was a significant treatment-gender interaction seen. Myalgia rates were slightly higher in women in both statin and placebo groups. In conclusion, the response of women to atorvastatin was similar to that of men, with slightly more discontinuations due to adverse events. Higher on-treatment LDL cholesterol was significantly associated with more CV events in both genders, but the association was stronger for stroke in women and for coronary heart disease death in men.

Objectives To study whether high-dose versus usual-dose statin treatment reduces the incidence of peripheral artery disease (PAD) and what is the effect of high-dose statin treatment on cardiovascular disease (CVD) outcome in patients with PAD. Methods and results In the Incremental Decrease in End Points Through Aggressive Lipid Lowering trial, 8888 post-myocardial infarction patients were randomised to high-dose or usual-dose statin therapy (atorvastatin 80 mg/day vs simvastatin 20–40 mg/day). We investigated the effect of high-dose versus usual-dose statins on the pre-specified outcome PAD incidence, and additionally performed a posthoc analysis of the efficacy of high-dose statins in reducing CVD risk among patients with PAD. During a median follow-up of 4.8 years, 94 patients (2.2%) receiving atorvastatin and 135 patients (3.2%) receiving simvastatin developed PAD (HR=0.70, 95% CI 0.53 to 0.91; p=0.007). The risk of major coronary events was almost twofold higher in patients with PAD at baseline, but was no longer significant after adjusting for the adverse cardiovascular risk profile. In PAD patients, major coronary events occurred in fewer patients in the atorvastatin group (14.4%) than in the simvastatin group (20.1%), but the difference did not reach statistical significance. (HR=0.68, 95% CI 0.41 to 1.11; p=0.13). Atorvastatin treatment significantly reduced overall cardiovascular (p=0.046) and coronary events (p=0.004), and coronary revascularisation (p=0.007) in these patients. Conclusions High-dose statin therapy with atorvastatin significantly reduced the incidence of PAD compared with usual-dose statin therapy with simvastatin. Patients with a history of PAD at baseline were at higher risk of future coronary events and this risk was reduced by high-dose atorvastatin treatment. Trial registration number NCT00159835 (URL: http://clinicaltrials.gov/show/NCT00159835).

A recent study has shown an association between high-potency statins and risk of acute kidney injury. However, these data are from observational studies, and it is not clear if similar signal is seen from randomized controlled trials. We evaluated the risk of renal-associated serious adverse events (SAEs) using statins versus placebo trials and the high-dose versus low-dose statin trials that were available to us. The outcome of interest was renal-related SAEs. The incidence of adverse events relating to kidney injury was determined through review of the adverse event database. The following outcomes were evaluated: (1) renal-related SAEs within 120 days of randomization (primary outcome), (2) renal-related SAEs after 120 days of randomization (secondary), and (3) drug discontinuation due to renal-related SAEs (secondary). There was no difference in the incidence of renal-related SAEs at 120 days (0.04% vs 0.10%, p = 0.162) between atorvastatin and placebo in the 24 placebo-controlled trials (10,345 patients on atorvastatin (10 to 80 mg/day) versus 8,945 patients on placebo) or in the high-dose versus low-dose statin trials including the Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) study (0.05% vs 0.02%, p = 0.625) or the Treating to New Targets (TNT) trial (0.0% vs 0.04%, p = 0.500) trial. Results were similar for renal-related SAEs after 120 days (placebo controlled trials [0.38% vs 0.36%, p = 0.905], IDEAL trial [0.56% vs 0.65%, p = 0.683], or the TNT trial [0.76% vs 1.04%, p = 0.168]) and for drug withdrawal due to renal-related SAE (placebo controlled trials [0.05% vs 0.04%, p = 1.00], IDEAL trial [0.02% vs 0.0%, p = 0.499], or the TNT trial [0.08% vs 0.12%, p = 0.754]). In conclusion, the results from clinical trials with data from 149,882 patient-years of follow-up fail to show any increase in renal-related SAEs with statins compared with controls.

Background Improvement in renal function and decreases in serum uric acid (SUA) have been reported following prolonged high-intensity statin (HMG-CoA reductase inhibitor) therapy. This post hoc analysis of the SAGE trial examined the effect of intensive versus less intensive statin therapy on renal function, safety, and laboratory parameters, including SUA, in elderly coronary artery disease (CAD) patients (65–85 years) with or without chronic kidney disease (CKD). Methods Patients were randomized to atorvastatin 80 mg/day or pravastatin 40 mg/day and treated for 12 months. Patients were stratified using Modification of Diet in Renal Disease (MDRD) estimated glomerular filtration rates (eGFRs) in CKD (eGFR <60 mL/min/1.73 m 2 ) and non-CKD populations. Results Of the 893 patients randomized, 858 had complete renal data and 418 of 858 (49 %) had CKD (99 % Stage 3). Over 12 months, eGFR increased with atorvastatin and remained stable with pravastatin (+2.38 vs. +0.18 mL/min/1.73 m 2 , respectively; p  < 0.0001). MDRD eGFR improved significantly in both CKD treatment arms; however, the increased eGFR in patients without CKD was significantly greater with atorvastatin (+2.08 mL/min/1.73 m 2 ) than with pravastatin (−1.04 mL/min/1.73 m 2 ). Modest reductions in SUA were observed in both treatment arms, but a greater fall occurred with atorvastatin than with pravastatin (−0.52 vs. −0.09 mg/dL, p  < 0.0001). Change in SUA correlated negatively with changes in eGFR and positively with changes in low-density lipoprotein cholesterol. Reports of myalgia were rare (3.6 % CKD; 5.7 % non-CKD), and there were no episodes of rhabdomyolysis. Elevated serum alanine and aspartate transaminase to >3 times the upper limit of normal occurred in 4.4 % of atorvastatin- and 0.2 % of pravastatin-treated patients. Conclusion Intensive management of dyslipidemia in older patients with stable coronary heart disease may have beneficial effects on renal function and SUA.

The predictive value of early functional improvement for treatment success at week 8 was assessed in a pooled analysis in patients with major depressive disorder (MDD). Data were pooled from 7 double-blind studies in adult patients with MDD randomly assigned to desvenlafaxine 50 mg/d or placebo. Four levels of treatment success were determined at week 8 for patients with baseline Sheehan Disability Scale (SDS) score > 12 (N = 2156): functional response (SDS ≤12 and ≥50% improvement in SDS), functional/depression response (SDS ≤12 and ≥50% improvement in both SDS and 17-item Hamilton Rating Scale for Depression [HAM-D17] score), functional remission (SDS < 7), and functional/depression remission (SDS < 7 and HAM-D17 ≤7). Week 2 improvement in SDS was evaluated as a predictor of later functional response/remission using receiver operating characteristic analysis. Odds ratios (ORs) of the predictability of improvement thresholds were computed from a logistic regression model. The proportion of patients achieving each level of treatment success was significantly greater for patients treated with desvenlafaxine (40%, 32%, 23%, 15%, respectively) vs placebo (31%, 22%, 17%, 10%; all P ≤ 0.002). Early change in SDS was a highly significant predictor of functional response/remission (ORs, 0.958-0.970; all P < 0.0001). Discussion Patients' early functional response to desvenlafaxine 50 mg/d is predictive of treatment success.

Alopecia areata is characterised by non-scarring loss of scalp, face, or body hair. We investigated the efficacy and safety of ritlecitinib, an oral, selective dual JAK3/TEC family kinase inhibitor, in patients with alopecia areata. In this randomised, double-blind, multicentre, phase 2b–3 trial done at 118 sites in 18 countries, patients aged 12 years and older with alopecia areata and at least 50% scalp hair loss were randomly assigned to oral ritlecitinib or placebo once-daily for 24 weeks, with or without a 4-week loading dose (50 mg, 30 mg, 10 mg, 200 mg loading dose followed by 50 mg, or 200 mg loading dose followed by 30 mg), followed by a 24-week extension period during which ritlecitinib groups continued their assigned doses and patients initially assigned to placebo switched to ritlecitinib 50 mg or 200 mg loading dose followed by 50 mg. Randomisation was done by use of an interactive response system and was stratified by baseline disease severity and age. The sponsor, patients, and investigators were masked to treatment, and all patients received the same number of tablets to maintain masking. The primary endpoint was Severity of Alopecia Tool (SALT) score 20 or less at week 24. The primary endpoint was assessed in all assigned patients, regardless of whether they received treatment. This study was registered with ClinicalTrials.gov, NCT03732807. Between Dec 3, 2018, and June 24, 2021, 1097 patients were screened and 718 were randomly assigned to receive ritlecitinib 200 mg + 50 mg (n=132), 200 mg + 30 mg (n=130), 50 mg (n=130), 30 mg (n=132), 10 mg (n=63), placebo to 50 mg (n=66), or placebo to 200 mg + 50 mg (n=65). 446 (62%) of 718 patients were female and 272 (38%) were male. 488 (68%) were White, 186 (26%) were Asian, and 27 (4%) were Black or African American. Of 718 patients randomly assigned, 104 patients discontinued treatment (34 withdrew, 19 adverse events [AEs], 12 physician decision, 12 lack of efficacy, 13 lost to follow up, five rolled over to long-term study transfer, four pregnancies, two protocol deviations, one declined to attend follow-up due to COVID-19, one attended last visit very late due to COVID-19, and one non-compliance). At week 24, 38 (31%) of 124 patients in the ritlecitinib 200 mg + 50 mg group, 27 (22%) of 121 patients in the 200 mg + 30 mg group, 29 (23%) of 124 patients in the 50 mg group, 17 (14%) of 119 patients in the 30 mg group, and two (2%) of 130 patients in the placebo group had a response based on SALT score 20 or less. The difference in response rate based on SALT score 20 or less between the placebo and the ritlecitinib 200 mg + 50 mg group was 29·1% (95% CI 21·2–37·9; p<0·0001), 20·8% (13·7–29·2; p<0·0001) for the 200 mg + 30 mg group, 21·9% (14·7–30·2; p<0·0001) for the 50 mg group, and 12·8% (6·7–20·4; p=0·0002) for the 30 mg group. Up to week 48 and including the follow-up period, AEs had been reported in 108 (82%) of 131 patients in the ritlecitinib 200 mg + 50 mg group, 105 (81%) of 129 patients in the 200 mg + 30 mg group, 110 (85%) of 130 patients in the 50 mg group, 106 (80%) of 132 patients in the 30 mg group, 47 (76%) of 62 patients in the 10 mg group, 54 (83%) of 65 patients placebo to ritlecitinib 200 mg + 50 mg in the extension period, and 57 (86%) of 66 patients in the placebo to 50 mg group. The incidence of each AE was similar between groups, and there were no deaths. Ritlecitinib was effective and well tolerated in patients aged 12 years and older with alopecia areata. Ritlecitinib might be a suitable treatment option for alopecia areata in patients who are candidates for systemic therapy. Pfizer.

Most patients with chest pain do not have acute myocardial infarction (AMI), yet post-AMI rule-out disposition remains variable. Detectable but sub-99th percentile high-sensitivity cardiac troponin I (hs-cTnI) provides additional prognostic information. We evaluated the economic value of hs-cTnI-guided hospitalizations among non-AMI patients. We analyzed 1481 non-AMI chest pain visits with detectable baseline hs-cTnI across 29 U.S. emergency departments (2014–2016) in the prospective HIGH-US trial using the Atellica IM TnIH assay(Siemens Healthcare Diagnostics, Tarrytown, NY, US). We compared observed standard-of-care admissions with modeled pathways incorporating hs-cTnI thresholds and risk scores, assessing admission rates, costs, and diagnostic accuracy for 30-day death/MI. Overall, 1.0% (n = 15/1481) experienced 30-day death/MI. Standard-of-care admitted 59% of patients with 93% sensitivity and 41% specificity. The modeled pathway using hs-cTnI ≥ 5 ng/L plus non-low risk scores was associated with reduced projected admission of 41%, higher specificity of 60%, and the same 93% sensitivity. Estimated per-patient diagnostic costs were lower under Scenario 1 (noninvasive diagnostic testing only;$1025 vs. $ 1139) and under Scenario 2 (including inpatient/invasive procedures;$2672 vs. $ 3536). In subgroups, higher hs-cTnI thresholds conferred further economic benefit without compromising sensitivity. Incorporating sub-99th percentile hs-cTnI thresholds alongside risk scores may support more efficient resource use while maintaining safety, although findings require prospective validation.

Abstract Background Increased neurofilament light chain (NfL) in cerebrospinal fluid and blood indicates recent neuroinflammatory damage and is prognostic of disease worsening (JAMA Neurol 2023;80:1317–25). These studies evaluate the analytical performance of the Siemens Healthineers Atellica IM NfL assay, testing serum and plasma, on the Atellica IM analyzer. Methods Detection capability, linearity, dilution recovery, precision, interfering substance testing, specimen equivalence, method comparison studies, and determination of expected values are all described and performed according to CLSI standards. Results The limit of blank, detection, and quantitation were 1.5, 2.0, and 3.0 pg/mL, respectively. The analytical measuring interval was 3.0 to 300.0 pg/mL with on-board dilutions extending the reportable range to 3000 pg/mL. Repeatability and within-lab precision ranged from 0.9% to 5.7% CV and 1.5% to 8.6% CV, respectively. No significant interference was detected for biotin or 38 other substances. Serum SST and plasma EDTA samples provided equivalent NfL results. Comparison of the NfL assay across Siemens Healthineers platforms (Atellica IM, ADVIA Centaur XP/XPT systems) showed strong alignment; the Atellica IM NfL assay also strongly aligns to the early phase certified reference material (Clin Chem Lab Med 2023;61:1245–54). Age-specific expected values for healthy adults were provided, with an overall central 95th percentile range of 3.7 to 18.9 pg/mL. Conclusion The Siemens Healthineers Atellica IM NfL assay demonstrated strong performance in all categories of assay development and verification; importantly, results from both healthy and multiple sclerosis patients fall within the reportable range. The Atellica IM NfL assay is for in vitro diagnostic use in the quantitative measurement of NfL in human serum and plasma (EDTA) using the Atellica IM analyzer.