An "Inclisiran First" Strategy vs Usual Care in Patients With Atherosclerotic Cardiovascular Disease.

BACKGROUND: Most patients with atherosclerotic cardiovascular disease fail to achieve guideline-directed low-density lipoprotein cholesterol (LDL-C) goals. Twice-yearly inclisiran lowers LDL-C by ∼50% when added to statins. OBJECTIVES: This study evaluated the effectiveness of an "inclisiran first" implementation strategy (adding inclisiran immediately upon failure to reach LDL-C <70 mg/dL despite receiving maximally tolerated statins) vs representative usual care in U.S. patients with atherosclerotic cardiovascular disease. METHODS: VICTORION-INITIATE, a prospective, pragmatically designed trial, randomized patients 1:1 to inclisiran (284 mg at days 0, 90, and 270) plus usual care (lipid management at treating physician's discretion) vs usual care alone. Primary endpoints were percentage change in LDL-C from baseline and statin discontinuation rates. RESULTS: We randomized 450 patients (30.9% women, 12.4% Black, 15.3% Hispanic); mean baseline LDL-C was 97.4 mg/dL. The "inclisiran first" strategy led to significantly greater reductions in LDL-C from baseline to day 330 vs usual care (60.0% vs 7.0%; P < 0.001). Statin discontinuation rates with "inclisiran first" (6.0%) were noninferior vs usual care (16.7%). More "inclisiran first" patients achieved LDL-C goals vs usual care (<70 mg/dL: 81.8% vs 22.2%; <55 mg/dL: 71.6% vs 8.9%; P < 0.001). Treatment-emergent adverse event (TEAE) and serious TEAE rates compared similarly between treatment strategies (62.8% vs 53.7% and 11.5% vs 13.4%, respectively). Injection-site TEAEs and TEAEs causing treatment withdrawal occurred more commonly with "inclisiran first" than usual care (10.3% vs 0.0% and 2.6% vs 0.0%, respectively). CONCLUSIONS: An "inclisiran first" implementation strategy led to greater LDL-C lowering compared with usual care without discouraging statin use or raising new safety concerns. (A Randomized, Multicenter, Open-label Trial Comparing the Effectiveness of an "Inclisiran First" Implementation Strategy to Usual Care on LDL Cholesterol [LDL-C] in Patients With Atherosclerotic Cardiovascular Disease and Elevated LDL-C [≥70 mg/dL] Despite Receiving Maximally Tolerated Statin Therapy [VICTORION-INITIATE]; NCT04929249).

Cyclooxygenase-2 (COX-2) levels before and after chemotherapy: a study in rectal cancer.

OBJECTIVES: Induction of cyclooxygenase-2 (COX-2) by inflammatory mediators, oncogenes, and carcinogens has been demonstrated in preclinical models. However, there are limited clinical data regarding COX-2 induction by chemotherapy or radiation. Experimental data suggest cross-talk between the EGFR and COX-2 pathways. The aim of this study was to analyze the expression of COX-2 before and after chemoradiation (CRT) and correlate the same with tumor (T) down-staging and survival. Similar data were obtained for EGFR expression before and after chemoradiation. METHODS: Archival paraffin-embedded tumor specimens from patients undergoing CRT between 1995 and 2001 were analyzed. COX-2 expression was measured by immunohistochemistry (IHC), using the 160112 COX-2 mouse monoclonal antibody. For EGFR, we used mouse monoclonal Ab-10. Standard immunoperoxidase technique was used to detect the avidin- biotin peroxidase complex. Staining in tumor tissue was visually scored and confirmed by an image analyzer (ACIS; ChromaVision Medical Systems, Inc, San Juan Capistrano, CA). RESULTS: Twenty pretreatment biopsy samples from rectal cancer patients and their paired, post-CRT surgical specimens (n = 17) were analyzed. Three cases had no primary tumor after CRT. COX-2 expression was noted in 19 of 20 pretreatment samples and 17 of 17 surgical specimens. EGFR expression was noted in 10 cases pretreatment. Six patients with weakly positive COX-2 expression pretreatment had increased COX-2 expression after CRT, whereas in 1 patient the expression decreased after CRT. No EGFR induction was noted. There was no statistical association between EGFR and COX-2 expression in this data set. Median survival for the entire cohort was 38.9 months. There was no difference in survival between the COX-2 induced and noninduced groups. CONCLUSIONS: COX-2 induction was seen with CRT in this population of rectal cancer patients. Prognostic significance of this induction remains to be defined in a larger cohort.

Prevalence of positional sleep apnea in patients undergoing polysomnography.

STUDY OBJECTIVES: The primary aim of this study was to determine the prevalence of positional obstructive sleep apnea using a functional definition. Positional sleep apnea was defined as a total apnea-hypopnea index (AHI) > or = 5 with a > 50% reduction in the AHI between the supine and nonsupine postures, and an AHI that normalizes (AHI < 5) in the nonsupine posture. A secondary aim was to determine if positional sleep apnea can be diagnosed accurately during a split-night study. DESIGN: Retrospective chart review. SETTING: Two sleep centers in Buffalo, NY, one a Veterans Affairs Western New York Healthcare System Sleep Center (VAWNY) and the other a freestanding ambulatory center (Associated Sleep Center [ASC]). PATIENTS: Three hundred twenty-six patients from the VAWNY, including 57 patients who underwent a split-night study and 242 patients from the ASC who underwent polysomnography. INTERVENTIONS: None. MEASUREMENTS: Patient characteristics and sleep study results. RESULTS: Positional sleep apnea was seen in 49 of 99 patients (49.5%) with mild sleep apnea (AHI, 5 to 15/h), 14 of 72 patients (19.4%) with moderate sleep apnea (AHI, 15 to 30/h), and 5 of 77 patients (6.5%) with severe sleep apnea (AHI > 30/h). Sufficient sleep (> 15 min) in both postures was not seen in 104 of 269 patients (38.7%) and 80 of 242 overnight studies (33.1%) at the VAWNY and ASC, respectively, and was not seen in 47 of 57 split-night studies (82.5%). The percentage of studies with insufficient sleep in both postures was significantly greater for split-night studies (p < 0.0001). CONCLUSIONS: Positional sleep apnea is common particularly in patients with mild disease. Positional sleep apnea cannot usually be assessed during a split-night study.