Premature Ticagrelor Discontinuation in Secondary Prevention of Atherosclerotic CVD: JACC Review Topic of the Week

Ticagrelor is a cornerstone of modern antithrombotic therapy alongside aspirin in patients with acute coronary syndrome and after percutaneous coronary intervention. Adverse effects such as bleeding and dyspnea have been associated with premature ticagrelor discontinuation, which may limit any potential advantage of ticagrelor over clopidogrel. The randomized trials of ticagrelor captured adverse events, offering the opportunity to more precisely quantify these effects across studies. Therefore, a meta-analysis of 4 randomized clinical trials of ticagrelor conducted between January 2007 and June 2017 was performed to quantify the incidence and causes of premature ticagrelor discontinuation. Among 66,870 patients followed for a median 18 months, premature ticagrelor discontinuation was seen in 25%; bleeding was the most common cause of discontinuation followed by dyspnea. Versus the comparators, the relative risk of dyspnea-related discontinuation during follow-up was 6.4-fold higher, the relative risk of bleeding was 3.2-fold higher, and the relative risk of discontinuation due to any adverse event was 59% higher for patients receiving ticagrelor. Understanding these potential barriers to adherence to ticagrelor is crucial for informed patient-physician decision making and can inform future efforts to improve ticagrelor adherence. This review discusses the incidence, causes, and biological mechanisms of ticagrelor-related adverse effects and offers strategies to improve adherence to ticagrelor.     

Prevention of biochemical changes in gamma-irradiated rats by some metal complexes.

The formation of superoxide partially accounts for the well-known oxygen enhancement of radiation-induced biochemical changes and cell damage. Radioprotective effects of copper (II), manganese (IV) or vanadium (IV) complexes, of superoxide dismutase-mimetic activity, on body weight, survival rate and some biochemical parameters in pre-treated irradiated, untreated irradiated and treated non-irradiated female albino rats have been studied 24 h after whole body gamma-irradiation at a dose level of 6 Gy. Survival time, body weight, red blood cell (RBC) and white blood cell (WBC) counts, hemoglobin (Hb) concentration, percentage of hematocrit (Hct%), reduced glutathione (GSH), serum total protein, albumin, globulin (G), blood urea, creatinine and cholesterol were estimated, as well as the activities of blood superoxide dismutase (SOD), glutamate-oxaloacetic (GOT) and glutamate-pyruvic (GPT) transaminases, and alkaline phosphatase were assessed. A significant decline was shown in body weight, survival rate, the mean values of RBC and WBC counts, Hb and Hct percentages, and GSH concentration, as well as blood SOD activity, in whole body gamma-irradiated rats compared with the control non-irradiated rat group. The mean activity values of alkaline phosphatase, GOT and GPT, as well as the average values of blood urea, creatinine, total cholesterol, total protein and globulin were significantly elevated, while the average values of albumin and the albumin/globulin ratio were decreased in gamma-irradiated rats compared with the corresponding values of the normal control rat group. Pretreatment of rats with either manganese or vanadium complexes resulted in a significant increase in survival rate and body weight over that of the non-treated irradiated rat group. Pretreatment of rats with copper (II), manganese (IV) or vanadium (IV) complexes caused a significant increase in RBC and WBC counts, Hb concentration, HCt (%), GSH content and SOD activity in blood when compared to the irradiated rat group without treatment. The administration of copper (II), manganese (IV) or vanadium (IV) complexes prior to irradiation exposure resulted in a significant decrease in GOT and GPT activities in addition to blood urea, creatinine, cholesterol, globulin and total protein contents, while each complex exhibited a significant increase in plasma alkaline phosphatase, albumin, and the albumin/globulin ratio compared to the untreated irradiated rat group. Administration of vanadium (IV), manganese (IV) or copper (II) complexes in non-irradiated rats caused a significant increase in SOD activity without changing other biochemical parameters compared with the corresponding values of the normal control rat group. We conclude that these metallo-elements, particularly manganese (IV) and vanadium (IV) complexes of 2-methylaminopyridine, have radiation protection and radiation recovery. Furthermore, these metal complexes offer a new approach to overcome the pathological effects of ionizing radiation and suggest their use as a physiological approach to preventing or perhaps predominantly facilitating recovery from radiation injury.     

Final score in laparoscopic cholecystectomy

Background: The role of intraoperative fluorocholangiography (IOC) in laparoscopic cholecystectomy (LC) is controversial. We evaluated the use of IOC at an institution where the study is performed routinely. Methods: Records of all patients undergoing LC during a 3-year period ending January 1, 1996 were reviewed. Results: A total of 1207 patients received IOC, whereas 116 patients did not. IOC findings were categorized as follows: normal, 1016 cases (84%); CBD stone, 149 cases (12.3%); anomalies, 23 cases (1.9%); duodenal diverticula, 10 cases (0.8%); ductal strictures, four cases (0.3%); and CBD diverticula, 5 cases (0.4%). In the 116 patients who did not receive IOC, 35 of the procedures could not be performed, whereas 81 were not attempted. Of the 149 IOC that showed CBD stones, two were false positives. Anomalies included accessory right hepatic ducts (11 cases), cystic ducts joining the right hepatic duct (seven cases), and abnormal cystic duct entries (five cases). Duct injuries occurred in 5 cases (0.4%), three before and two after IOC. Four injuries were minor; IOC prevented CBD transection. Conclusions: Routine IOC is feasible, safe, accurate, and provides critical information of immediate use during LC. By treating ductal stones at operation and identifying patients without CBD stones, IOC minimizes need for postoperative studies, including endoscopic retrograde cholangiography (ERC).     

Improved intracranial lesion characterization by tissue segmentation based on a 3D feature map

Our aim was to develop an accurate multispectral tissue segmentation method based on 3D feature maps. We utilized proton density (PD), T₂-weighted fast spin-echo (FSE), and T₁-weighted spin-echo images as inputs for segmentation. Phantom constructs, cadaver brains, an animal brain tumor model and both normal human brains and those from patients with either multiple sclerosis (MS) or primary brain tumors were analyzed with this technique. Initially, misregistration, RF inhomogeneity and image noise problems were addressed. Next, a qualified observer identified samples representing the tissues of interest. Finally, k-nearest neighbor algorithm (k-NN) was utilized to create a stack of color-coded segmented images. The inclusion of T₁ based images, as a third input, produced significant improvement in the delineation of tissues. In MS, our 3D technique was found to be far superior to that based on any combination of 2D feature maps (P < 0.001). We identified at least two distinctly different classes of lesions within the same MS plaque, representing different stages of the disease process. Further, we obtained the regional distribution of MS lesion burden and followed its changes over time. Neuropsychological aberrations were the clinical counterpart of the structural changes detected in segmentation. We could also delineate the margins of benign brain tumors. In malignant tumors, up to four abnormal tissues were identified: 1) a solid tumor core, 2) a cystic component, 3) edema in the white matter, and 4) areas of necrosis and hemorrhage. Subsequent neurosurgical exploration confirmed the distribution of tissues as predicted by this analysis.     

Comparison of dobutamine stress echocardiography and technetium-99m sestamibi single-photon emission tomography for the diagnosis of coronary artery disease in hypertensive patients with and without left ventricular hypertrophy

Stress echocardiography has been considered an accurate method for the diagnosis of coronary artery disease in hypertensive patients and in patients with left ventricular hypertrophy. In contrast, the specificity of myocardial perfusion scintigraphy in these patients has been questioned. The aim of this study was to compare the accuracy of these two imaging modalities in conjunction with dobutamine stress test for the diagnosis of coronary artery disease in hypertensive patients with and without left ventricular hypertrophy. Dobutamine (up to 40 μg kg^–1min^–1) stress echocardiography in conjunction with sestamibi (MIBI) single-photon emission tomography (SPET) was performed in 84 patients with the diagnosis of systemic hypertension who had been referred for evaluation of myocardial ischaemia. Ischaemia was defined as new or worsened wall motion abnormalities at echocardiography and reversible perfusion defects at SPET. Significant coronary artery disease (≥50% luminal diameter stenosis) was detected in 66 patients (79%). The sensitivity, specificity and accuracy of the ischaemic pattern at echocardiography for the diagnosis of coronary artery disease were 73% (CI 63%–82%), 83% (CI 75%–91%) and 75% (CI 66%–84%), those for MIBI were 67% (CI 57%–77%), 83% (CI 75%–91%) and 70% (CI 60%–80%) respectively (P = NS vs echocardiography). Significant stenosis was detected in 123 (49%) of the 252 analysed coronary arteries. The sensitivity, specificity and accuracy of echocardiography for the regional diagnosis of coronary artery disease were 63% (CI 56%–69%), 90% (CI 86%–94%) and 77% (CI 72%–82%). Those for MIBI were 58% (CI 51%–64%), 91% (CI 87%–94%) and 75% (CI 69%–80) respectively (P = NS vs echocardiography). Left ventricular hypertrophy was detected in 59 patients (70%) by echocardiography and did not influence the overall or regional specificity of echocardiography or MIBI SPET. It is concluded that in hypertensive patients, dobutamine stress echocardiography and MIBI SPET have a comparable accuracy for the overall and regional diagnosis of coronary artery disease. Hypertensive patients with or without left ventricular hypertrophy should not be considered unsuitable candidates for stress myocardial perfusion scintigraphy. Received 10 July and in revised form 19 September 1997     

Long-term results of laryngotracheal resection for benign stenosis.

OBJECTIVE: We report the long-term results of our 16-year experience with laryngotracheal resection for benign stenosis. METHODS: Between 1991 and 2006, 35 consecutive patients (19 males, 16 females) underwent laryngotracheal resection for subglottic postintubation (32) or idiopathic (3) stenosis. Mean age was 43 years (range 14-71). At the time of surgery 13 patients presented with tracheostomy and 7 with a Dumon stent. The upper limit of the stenosis was from 0.6 to 1.5 cm below the vocal cords. The length of airway resection ranged between 1.5 and 6 cm. Suprahyoid release was performed in two patients and pericardial release in one. Nine patients had psychiatric and/or neurological post-coma disorders. Mean follow-up is over 5 years (61 months; range 3-194). RESULTS: There was no perioperative mortality. Thirty patients (85.7%) had excellent or good anatomic and functional results. Four patients (11.4%) presented restenosis at a distance of 25-110 days from the operation. Restenosis was successfully treated by endoscopic procedures in all four patients. One patient (2.9%) presented anastomotic dehiscence that required temporary tracheostomy closed after 1 year with no sequelae. Three patients (8.4%) had wound infection. Long-term follow-up was uneventful also in patients who had early complications. CONCLUSIONS: Long-term follow-up confirms that laryngotracheal resection is the definitive curative treatment for benign subglottic stenosis. Surgical complications can be successfully managed by non-operative procedures. Despite the occurrence of early complications, excellent and stable results can still be obtained at long term.     

Differentiation of interstistial cells and stromal proteins in the secondary septum of early postnatal rat: Effect of maternal chronic exposure to whole cigarette smoke

The intention of this investigation was to ascertain the effect of maternal exposure to cigarette smoke on the early postnatal morphogenesis of pulmonary interstitum in offspring. Female rats were chronically exposed to whole cigraette smoke. Offspring of these and control animals were sacrificed at postnatal day 15, and their tissues were prepared for quantitative and qualitative analyses. Results indicate a diminished quantitative representaion of parenchymal tissue (P <0.01) and a slower pace of secondary septal growth (P <0.07) in the experimental lung. Furthermore, a greater cellular volume density (P <0.0002) was ascertained for the experimental septal inerstitium. There was proportionately less of elastin substances (P < 0.009), collagen together with basal laminae (P < 0.0008), and nonfibrillar, amorphous matrix (P < 0.02) in the experimental extracellular stroma. Fribrillar collagen and nonfibrillar matrix were represented quantitatively 6.3 times more in the experimental extracellular interstitum than elastin, whereas that ratio for the control tissue was only 4.2. Most experimental interstitial cells (80%) contained numerous lipid globules, which, in contrast, were only occasionally present in control cells (7.3%). Experimental cells, consequently, possessed a larger cross-sectional diameter and a smaller nucleus-to-cytoplasm volume ratio than control cells. These divergent developmental patterns are possibly suggestive of a delayed differentiation of interstitial cells and a modified production to degradation balance of stromal proteins in offspring of animals chronically exposed to whole cigarette smoke.