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

Effects of Once-Weekly Exenatide on Cardiovascular Outcomes in Type 2 Diabetes.

Abstract BACKGROUND: The cardiovascular effects of adding once-weekly treatment with exenatide to usual care in patients with type 2 diabetes are unknown. METHODS: We randomly assigned patients with type 2 diabetes, with or without previous cardiovascular disease, to receive subcutaneous injections of extended-release exenatide at a dose of 2 mg or matching placebo once weekly. The primary composite outcome was the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The coprimary hypotheses were that exenatide, administered once weekly, would be noninferior to placebo with respect to safety and superior to placebo with respect to efficacy. RESULTS: In all, 14,752 patients (of whom 10,782 [73.1%] had previous cardiovascular disease) were followed for a median of 3.2 years (interquartile range, 2.2 to 4.4). A primary composite outcome event occurred in 839 of 7356 patients (11.4%; 3.7 events per 100 person-years) in the exenatide group and in 905 of 7396 patients (12.2%; 4.0 events per 100 person-years) in the placebo group (hazard ratio, 0.91; 95% confidence interval [CI], 0.83 to 1.00), with the intention-to-treat analysis indicating that exenatide, administered once weekly, was noninferior to placebo with respect to safety (P<0.001 for noninferiority) but was not superior to placebo with respect to efficacy (P=0.06 for superiority). The rates of death from cardiovascular causes, fatal or nonfatal myocardial infarction, fatal or nonfatal stroke, hospitalization for heart failure, and hospitalization for acute coronary syndrome, and the incidence of acute pancreatitis, pancreatic cancer, medullary thyroid carcinoma, and serious adverse events did not differ significantly between the two groups. CONCLUSIONS: Among patients with type 2 diabetes with or without previous cardiovascular disease, the incidence of major adverse cardiovascular events did not differ significantly between patients who received exenatide and those who received placebo. (Funded by Amylin Pharmaceuticals; EXSCEL ClinicalTrials.gov number, NCT01144338 .)

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

Innovative concepts for diagnosis and treatment of aggressive pituitary adenomas

Hypophysenadenome sind endokrine Tumore, die aus parenchymalen Zellen der Adenohypophyse entstehen. Eine eindeutige Invasivität in angrenzende Strukturen ist der wichtigste Grund für eine unvollständige Resektion und den Rückgang der Remissionsrate. In einer nicht zu unterschätzenden Gruppe von invasiven Hypophysenadenomen kommt es trotz verschiedener Behandlungsmodalitäten, wie: Operationen, medikamentöser Behandlung und Bestrahlung /radiochirurgische Eingriffe, zu Rezidiven. Diese aggressiven Tumore stellen eine deutliche therapeutische Herausforderung für das interdisziplinäre Team dar. Im Rahmen dieser PhD-Arbeit untersuchten wir innovative Konzepte für die Diagnose und Behandlung von Hypophysenadenomen: Wir haben ein Protokoll für die intraoperative Neuronavigation entwickelt, untersucht die Möglichkeiten der direkten Visualisierung von parasellären Strukturen unter der Verwendung von endoskopischen Optiken und überarbeiteten damit eine weltweit anerkannte Klassifikation. Darüber hinaus haben wir gezeigt, dass die niedrige bis moderate Expression des Markers MGMT signifikant mit Invasivität und Rezidivneigung in der Untergruppe der hormonell aktiven Makrohypophysenadenome korreliert. Abschließend stellen die Ergebnisse dieser PhD-Arbeit neuartige Erkenntnisse über die Diagnose und Behandlung von im Besonderen aggressiven Hypophysenadenomen in einem frühen Stadium der Krankheit dar.Pituitary adenomas are endocrine tumours that arise from parenchymal cells of the anterior pituitary gland. Overt invasion into surrounding structures is found to be the most important reason for incomplete resection and a drop in cure rate. In an underestimated number of cases, invasive adenomas continue to recur despite multiple treatment modalities such as surgeries, medical treatments and radiation/radiosurgical therapies. These aggressive tumours pose a significant therapeutic challenge to the interdisciplinary team. In the frame of this doctoral thesis, we investigated innovative concepts for diagnosis and treatment of pituitary adenomas: We developed a protocol for intraoperative neuronavigation, investigated the possibilities of direct visualization of parasellar structures with use of endoscopic optics and thereby revised a worldwide admitted classification. Furthermore, we found that low-to-moderate expression of the marker MGMT significantly correlated with surgical invasiveness and recurrence in the subgroup of functioning pituitary macroadenomas. In conclusion the results of this doctoral thesis provide novel insight on diagnosing and treating especially aggressive pituitary adenomas at an early stage of disease.submitted by Alexander Sergeus Gregor MickoAbweichender Titel laut Übersetzung der Verfasserin/des VerfassersMedizinische Universität Wien, Dissertation, 2017OeBB(VLID)249964

Management of acute subdural hematoma in incarcerated patients

Introduction: Incarcerated patients have been documented to have higher rates of mental illness, substance abuse disorders, trauma, and chronic illnesses compared to non-incarcerated populations. In this study, we evaluated the incidence of subdural hematoma (SDH) in incarcerated patients and compared the outcomes of these patients to those of non-incarcerated patients. Methods: We conducted a retrospective cohort study of incarcerated patients admitted to a hospital with acute SDH using the Nationwide Readmissions Database between 2016−2017. Nearest-neighbor propensity score matching for demographics was implemented to identify non-incarcerated control patients admitted with SDH. Analysis used chi-squared testing, Mann-Whitney U testing, and generalized binomial regression modeling. Results: A total of 962 incarcerated and non-incarcerated patients were identified at primary admission. No significant difference was found between the two cohorts with regards to rates of neurosurgical complications or readmissions. Incarcerated patients were found to receive a significantly lower number of procedures, including respiratory ventilation, intubation, central venous line placement, and imaging, during their primary admission (NPR = 2.7 ± 4.0) compared to non-incarcerated patients (NPR = 3.9 ± 4.9) (p = 0.00050), reduced length of stay (p = 0.0052), and reduced hospital costs (p = 0.00026) compared to non-incarcerated patients. Furthermore, female incarcerated patients with SDH had significantly worse outcomes compared to male patients with SDH, including higher rates of mortality (p = 0.0017) and 30-day readmission rates (p = 0.041). Discussion: Our study suggests that incarcerated patients may receive significantly fewer diagnostic and supportive procedures while admitted for SDH and may be discharged sooner than non-incarcerated patients with SDH. In addition, outcomes following SDH within incarcerated patients may be significantly worse for females

MGMT assessment in pituitary adenomas : comparison of different immunohistochemistry fixation chemicals

Purpose Despite the established role of O6-methyl-guanine-DNA methyltransferase (MGMT) as a marker for temozolomide response, consensus of the most reliable method to assess MGMT expression in pituitary adenomas is still missing. Currently, immunohistochemistry (IHC) assessment of formaldehyde fixed tissue samples is most widely used in a semiquantitative description. As formaldehyde fails to completely preserve nucleic acids, RCL2, an alcohol-based formaldehyde-free fixative, has been proposed as a more reliable alternative in terms of cell stability. Furthermore, as the current method of IHC is semiquantitative and observer-dependent, pyrosequencing, an objective tool to evaluate the methylation status of the MGMT promoter, has emerged as a reliable and accurate alternative. The aim of this study was to validate the current IHC method for assessment of MGMT protein expression in pituitary adenomas. Methods The tissue samples of 8 macroadenomas with positive IHC MGMT expression (>50%) were investigated: first, we compared the time dependent stability of MGMT protein expression after pituitary adenoma removal between formaldehyde vs. RCL2. Then, we compared positive IHC MGMT expression with methylated promoter status using pyrosequencing. Results In the first 12 h after adenoma removal, tissue samples remained MGMT positive in significantly more samples when fixated with formaldehyde than with RCL2, respectively (96 vs. 81%, p=0.025). Conclusion Our data confirm that the current method using formaldehyde tissue fixation and IHC reveals stable and reliable results of MGMT assessment in pituitary adenomas.(VLID)358034

Molecules / Line Scan Raman Microspectroscopy for Label-Free Diagnosis of Human Pituitary Biopsies

Pituitary adenomas are neoplasia of the anterior pituitary gland and can be subdivided into hormone-producing tumors (lactotroph, corticotroph, gonadotroph, somatotroph, thyreotroph or plurihormonal) and hormone-inactive tumors (silent or null cell adenomas) based on their hormonal status. We therefore developed a line scan Raman microspectroscopy (LSRM) system to detect, discriminate and hyperspectrally visualize pituitary gland from pituitary adenomas based on molecular differences. By applying principal component analysis followed by a k-nearest neighbor algorithm, specific hormone states were identified and a clear discrimination between pituitary gland and various adenoma subtypes was achieved. The classifier yielded an accuracy of 95% for gland tissue and 8499% for adenoma subtypes. With an overall accuracy of 92%, our LSRM system has proven its potential to differentiate pituitary gland from pituitary adenomas. LSRM images based on the presence of specific Raman bands were created, and such images provided additional insight into the spatial distribution of particular molecular compounds. Pathological states could be molecularly differentiated and characterized with texture analysis evaluating Grey Level Cooccurrence Matrices for each LSRM image, as well as correlation coefficients between LSRM images.(VLID)491681