Oral anticoagulants for nonvalvular atrial fibrillation in frail elderly patients: insights from the ARISTOPHANES study.

BACKGROUND: Patient frailty amongst patients with nonvalvular atrial fibrillation (NVAF) is associated with adverse health outcomes and increased risk of mortality. Additional evidence is needed to evaluate effective and safe NVAF treatment in this patient population. OBJECTIVES: This subgroup analysis of the ARISTOPHANES study compared the risk of stroke/systemic embolism (S/SE) and major bleeding (MB) amongst frail NVAF patients prescribed nonvitamin K antagonist oral anticoagulants (NOACs) or warfarin. METHODS: This comparative retrospective observational study of frail, older NVAF patients who initiated apixaban, dabigatran, rivaroxaban or warfarin from 01JAN2013-30SEP2015 was conducted using Medicare and 3 US commercial claims databases. To compare each drug, 6 propensity score-matched (PSM) cohorts were created. Patient cohorts were pooled from 4 databases after PSM. Cox models were used to estimate hazard ratios (HR) of S/SE and MB. RESULTS: Amongst NVAF patients, 34% (N = 150 487) met frailty criteria. Apixaban and rivaroxaban were associated with a lower risk of S/SE vs warfarin (apixaban: HR: 0.61, 95% CI: 0.55-0.69; rivaroxaban: HR: 0.79, 95% CI: 0.72-0.87). For MB, apixaban (HR: 0.62, 95% CI: 0.57-0.66) and dabigatran (HR: 0.79, 95% CI: 0.70-0.89) were associated with a lower risk and rivaroxaban (HR: 1.14, 95% CI: 1.08-1.21) was associated with a higher risk vs warfarin. CONCLUSION: Amongst this cohort of frail NVAF patients, NOACs were associated with varying rates of stroke/SE and MB compared with warfarin. Due to the lack of real-world data regarding OAC treatment in frail patients, these results may inform clinical practice in the treatment of this patient population.

Inpatient and outpatient treatment patterns of cancer-associated thrombosis in the United States.

Low molecular weight heparins (LMWHs) and direct oral anticoagulants (DOACs) are among the recommended treatment options for cancer-associated thrombosis (CAT) in the 2019 National Comprehensive Care Network guidelines. Little is known about the current utilization of DOACs in CAT patients, particularly on the inpatient to outpatient therapy transition. This study assessed real-world treatment patterns of CAT in hospital/ED in adult cancer patients (≥ 18 years) diagnosed with CAT during a hospital visit in IQVIA's Hospital Charge Data Master database between July 1, 2015 and April 30, 2018, and followed their outpatient medical and pharmacy claims to evaluate the initial inpatient/ED and outpatient anticoagulants received within 3 months post-discharge. Results showed that LMWH and unfractionated heparin (UFH) were the most common initial inpatient/ED CAT treatments (35.2% and 27.4%, respectively), followed by DOACs (9.6%); 20.8% of patients received no anticoagulants. Most DOAC patients remained on DOACs from inpatient/ED to outpatient settings (71.4%), while 24.1%, 43.5%, and 0.1% of patients treated with LMWH, warfarin, or UFH respectively, remained on the same therapy after discharge. In addition, DOACs were the most common initial post-discharge outpatient therapy. Outpatient treatment persistence and adherence appeared higher in patients using DOACs or warfarin versus LMWH or UFH. This study shows that DOACs are used as an inpatient/ED treatment option for CAT, and are associated with less post-discharge treatment switching and higher persistence and adherence. Further research generating real-world evidence on the role of DOACs to help inform the complex CAT clinical treatment decisions is warranted.

Greater remission rates in patients with early versus long-standing disease in biologic-naive rheumatoid arthritis patients treated with abatacept: a post hoc analysis of randomized clinical trial data.

OBJECTIVES: Current aim of rheumatoid arthritis (RA) treatment is to achieve remission in as many patients as possible. Rates of remission and clinical outcomes after treatment with abatacept in biologic-naive rheumatoid arthritis (RA) patients with early disease and an inadequate response to methotrexate (MTX) versus patients with ≥ 10 years of disease were assessed. METHODS: Data from two trials assessing the efficacy of abatacept in MTX inadequate responders were pooled for this exploratory post hoc analysis. Patients with disease duration of ≤ 2 years at baseline (early disease), originally assigned to an abatacept approximately 10 mg/kg treatment arm and entered into a long-term extension (LTE), were compared with patients with ≥ 10 years of disease (long-standing RA). Remission, DAS28-CRP, ACR 70 responses and the Routine Assessment of Patient Index Data 3 (RAPID3), improvement in physical function as measured by the Health Assessment Questionnaire Disability Index (HAQ-DI). RESULTS: Twenty-three percent of these patients (n=108) had early disease. A higher percentage of patients with early disease achieved DAS28-CRP remission versus patients with long-standing disease (35.2% vs. 19.4% at year 1, p<0.01; 46.0% vs. 30.9% at year 3, p<0.05). In addition, a higher percentage of the subgroup with early RA achieved ACR70 responses. More patients with early RA had a meaningful improvement in their HAQ-DI (75.2% vs. 60.4%; p<0.05) and RAPID3 scores at one year (mean changes from baseline of -9.6 vs. -8.1; p=0.009). CONCLUSIONS: These data provide additional support for the possible use of abatacept in biologic-naive patients who have had inadequate response to MTX, earlier in their disease course.

Patient and physician perception of the infusion process of the biologic agents abatacept, infliximab, and rituximab for the treatment of rheumatoid arthritis.

OBJECTIVES: To assess the process related to each infusible biologic used in rheumatoid arthritis (RA) with regard to patient and physician engagement in the infusion process, ancillary services required, and participant preferences. METHODS: This was a cross-sectional survey of patients with RA and their physicians. Biologic-naïve patients with RA starting abatacept, infliximab, or rituximab were included. Both patients and physicians completed detailed questionnaires related to the infusion and satisfaction with the process. RESULTS: A total of 205 patients were enrolled: abatacept (n=102), infliximab (n=74), rituximab (n=29). Patients were primarily female (75%), Caucasian (85%), with a mean age of 58 years. Patients had a mean disease duration of approximately 8 years and had typically failed multiple DMARDs. Rituximab required the most pre-infusion preparation and the longest infusion time. Abatacept was associated with a shorter mean infusion time (42 minutes) than infliximab (131 minutes; p<0.0001) or rituximab (274 minutes; p<0.0001) and required less time away from work/home (p=0.01 and p<0.0001, respectively). Abatacept patients reported significantly less discomfort than rituximab patients (p=0.03), while discomfort was similar between abatacept and infliximab. From the physicians' perspective, compared to infliximab and rituximab abatacept was very easy to administer (57% vs. 27% and 5%, respectively), caused no pain/discomfort (52% vs. 42% and 31%), and had very infrequent infusion reactions (75% vs. 30% and 44%). CONCLUSION: The process involved in infusion administration, as perceived by both the patient and physician, seems to differ across the three infusible biologic agents and may have an impact on the decision-making process regarding which infusible biologic to use.

Kinetics of lymphohematopoietic progenitor cell populations in chronically irradiated RF/J mice.

Continuous protracted gamma irradiation (17.5 rad/22 h day for 28 days) resulted in significant life-shortening in RF/J mice due to lymphohematopoietic malignancies. The latency period of these neoplasms was decreased in irradiated RF/J versus unirradiated RF/J mice. No effect on leukemia incidence was observed in either irradiated or unirradiated CAF1 mice that served as control animals representing a strain with normal baseline lymphohematopoiesis. Lymphohematopoietic progenitor cell populations (CFU-GM and CFU-BL) were quantitated in unirradiated and chronically irradiated mice of both strains. The most remarkable differences in these parameters were seen with respect to CFU-BL. Unirradiated and irradiated RF/J mice produced over three times as many CFU-BL as CAF1 mice. Tremendously expanded lymphoid progenitor cell compartments in the RF/J mice may reflect the presence of numerically increased sensitive targets subject to radiation-induced damage and transformation. During a 12-week recovery period, CFU-BL and CFU-GM in the RF/J mice exhibited enhanced regenerative capabilities and overcompensatory responses that surpassed homeostatic baseline levels. Despite strain and strain X dose differences in CFU-BL and CFU-GM, no significant strain X dose relationships were seen in circulating leukocyte counts. This heightened proliferative activity and temporary overstimulation of radiation-damaged lymphohematopoietic tissues may allow sufficient promotional effect for leukemogenesis.

Seasonal variation in cell mediated immunity of clinically normal dogs.

A whole blood lectin-induced lymphocyte stimulation test, using Con A and PHA, was used to assess the cell mediated immune status of 52 beagle dogs over a period of 16 months. The data indicated the presence of a seasonal variation in immune response with the peak estimated to be in July and an estimated trough in January. The relative amplitudes around the mean, for the two mitogens, were about 50%, so that the responses on lymphocyte division ranged from 50 to 150% of the mean during the course of the year. The possible implications of this finding for human health are discussed.

The selective growth of human T lymphocyte colonies from whole blood in a semisolid culture system.

Human T lymphocyte colonies may be selectively grown from whole blood in a single phase semisolid culture system following stimulation with PHA-P, Con-A, or PPD. This technique eliminates the requirement for gradient-enriched lymphocyte fractions, and provides a sensitive system for the study of T lymphocyte progenitors that more closely approximates the in vivo milieu. Whole blood colonies were composed of lymphoblasts and mature lymphocytes. Individual colony cells, identified as T lymphocytes, lacked lipase and specific esterase activity, formed E rosettes, did not phagocytize latex beads, and were largely ANAE positive. Whole blood was plated at a final concentration of 3%. Optimal mitogen/antigen concentrations were 125 microgram Con-A, 80 microgram PHA-P and 50 microgram PPD/ml culture media. Peak colony growth occurred between days 7 and 8. Colony formation increased as a power function over a wide range of cell concentrations (5 x 10(3)-5 x 10(4) lymphocytes plated). Maximal whole blood colony formation occurred when 5 x 10(4)-10(5) lymphocytes were plated. There was a significant increase in the cloning efficiency using whole blood as compared to gradient-separated cells. This method has wide application for the study of radiation effects, lymphocyte alterations in various disease states, antigen recognition, and the induction and amplification of T cell function.

Oval corneal opacities in beagles. III. Histochemical demonstration of stromal lipids without hyperlipidemia.

We found oral stromal avascular corneal opacities in 128 eyes of 75 beagles from 497 studied. There were three morphologic types that progressed in severity with time; nebular, racetrack, and white arc. Histochemical study of the earliest morphologic type (nebular) revealed neutral fats, cholesterol, phospholipids, and sometimes fatty acids both intracellularly and extracellularly. We found no elevation of serum cholesterol or triglycerides except in dogs with the most advanced morphologic type (white arc) and no alteration in thyrometabolic function. We think that oval stromal opacities in beagle corneas are a primary disorder of corneal lipid metabolism closely resembling the central crystalline dystrophy of Schnyder and may be an animal model for this human disease.

In vitro radiation response studies on bone marrow fibroblasts (CFU-F) obtained from normal and chronically irradiated dogs.

The radiation resistance of bone marrow fibroblasts as measured by their proliferative potential was evaluated in chronically irradiated dogs. Bone marrows were obtained from eight dogs that had been chronically irradiated beginning at 21 days of gestation or after birth and eight age-matched controls. Of these irradiated dogs, four were either preleukemic or exhibited frank acute nonlymphocytic leukemia. The other four were clinically normal but demonstrated abnormalities in their marrow that could be attributed to radiation effects and/or other pathologic changes. Fibroblasts from six of the irradiated dogs were significantly more radioresistant than those of their controls. Five of these six dogs subsequently succumbed to hematopathologic disease, while the two irradiated dogs with normal fibroblasts remained clinically normal, suggesting that this observed radioresistance may be linked to the disease process.

Increased in vitro radioresistance of bone marrow fibroblastic progenitors (CFU-F) from patients with acute non-lymphocytic leukemia.

The proliferative potential following in vitro irradiation of bone marrow fibroblastic progenitors (CFU-F) derived from four patients with acute nonlymphocytic leukemia (ANLL) and seven nonleukemic subjects was compared. The CFU-F from the ANLL patients were significantly more radioresistant than the CFU-F from the nonleukemic subjects. The increased radioresistance in ANLL patients was evident in both the mean slope of the survival curve (control = -0.385, ANLL = -0.256) and in the Do values (control = 2.68 Gy, ANLL = 4.61 Gy). Thus CFU-F derived from ANLL patients differ from those derived from nonleukemics in both radioresistance and in granulopoietic effects as suggested from previous studies.

Four methods of measuring human corneal endothelial cells from specular photomicrographs.

We measured central corneal endothelial cell density and area from contact specular photomicrographs of ten normal and ten abnormal corneas, comparing the precision, cost, and speed of four methods: a rectangle, planimeter, digitizer, and cell sizer. The rectangle, planimeter, and digitizer gave results that differed less than 10% from each other; therefore, the three methods can be used interchangeably for clinical purposes. There are statistically significant differences among the three techniques that may be important in basic research. The cell sizer gave a rapid, less precise estimate of mean cell area and cell density. The planimeter and digitizer measured individual endothelial cell size, and the latter entered data directly into a computer that printed both a copy of the endothelial mosaic and a histogram of cell size frequency, and computed cell density and mean cell area. We make the following recommendations: Count cells in a rectangle used for routine clinical measurement. use a cell sizer for rough estimation, as in an eyebank setting. Use a computerized digitizer to study individual endothelial cell size.

Effects of X irradiation on the growth of normal and hyperplastic mouse mammary gland transplants.

To avoid the problems associated with whole-body radiation, pieces of X-irradiated normal or hyperplastic mammary tissue were transplanted to the host gland-free fat pad of nonexposed mice. The percentage of the fat pad filled by growth of the transplants at 4, 8, and 12 weeks after transplantation was measured. Growth of lobule transplants was moderately inhibited by 4 Gy. While some of the lobules survived 12 Gy, their growth was severely inhibited. The hyperplastic outgrowth lines were variable but more resistant than lobules to growth retardation. Line Z5D was more susceptible than D1, and Z5C1 was least susceptible, with 88% growing well after 12 Gy. In order to distinguish between transient and permanent growth retardation, tissue was taken from the irradiated and control transplants and retransplanted to new hosts without further radiation. The second generation of X-ray-exposed tissue filled more of the fat pad than the first-generation transplants, but significantly less than the nonexposed controls. The experiments described provide a means of demonstrating X-ray-induced changes in the mammary gland from growth inhibition to carcinogenesis.

Spontaneous cell-mediated cytolysis by peripheral blood cells obtained from whole-body chronically irradiated beagle dogs.

The level of natural killer (NK) activity of continuously gamma-irradiated (whole body) beagle dogs and their nonirradiated controls was studied. For analytical purposes, irradiated dogs were segregated into groups according to their clinical status: clinically normal, hypocellular, or with acute non-lymphocytic leukemia. Since unirradiated control animals exhibited a wide range of NK responses, the data from each irradiated animal were compared to its own age-matched or litter-matched unirradiated control. Of the eight clinically normal irradiated dogs (median = 146% activity of control) only one animal had a NK activity lower than that of its control. The hypocellular group (n = 5, median = 21.8% of control) and the leukemic group (n = 4, median = 52.5% of control) each contained one responder with higher activity than its control. The difference between the percentage of control of the clinically normal and clinically abnormal dogs was found to be significant (P less than 0.05). There is a negative correlation between the NK results obtained and the total accumulated dose of radiation at the time of sampling (correlation coefficient = -0.739, P less than 0.01), suggesting a radiation effect upon natural killer activity, which is evidence by enhancement at lower doses and depression at higher doses of irradiation.

Bone sarcoma characteristics and distribution in beagles injected with radium-226.

A total of 155 primary bone sarcomas were found in 131 of the 246 beagles injected with 226Ra and 5 primary bone sarcomas were found in 4 of the 158 unexposed controls. Of these 155 bone sarcomas, 146 (94%) were osteosarcomas and 9 were non-osteosarcomas. An additional 31 primary bone sarcomas (28 osteosarcomas) developed in 44 dogs terminated from the main study because of limb amputation for bone sarcoma. Non-osteosarcomas predominated in both the controls and the second lowest of six logarithmically increasing dose levels (there were no bone sarcomas in the lowest dose group). Osteosarcomas predominated at the higher dose levels, and incidence tended to increase as dose increased. The 146 osteosarcomas were distributed quite evenly between males and females (72:74). Of the 9 non-osteosarcomas, 6 occurred in males and 3 in females. The ratio of bone sarcomas of the appendicular skeleton to those in the axial skeleton was 110:45, with osteosarcomas occurring more often in the appendicular skeleton (108:38). Cases of multiple primary bone sarcomas in dogs injected with 226Ra were found only in the four highest dose groups. Amputations were performed on 44 of the 96 dogs (94 injected and 2 unexposed) that developed appendicular bone sarcomas. A statistical study of the distribution of bone sarcomas among 16 separate bone groups showed a statistically significant correlation to cancellous skeletal surface, but the variability among bone groups was too large for this relationship to be of real predictive value. It is postulated that the distribution of bone sarcomas reflects primarily the relative cell division rates in the bone groups and secondarily the radiation dose distribution, with the highest occurrence of bone sarcoma in the humeri, pelvis, femora and tibiae/fibular tarsal, and no occurrence in the coccygeal vertebrae, sternum, forepaws or hindpaws.

Bone sarcoma characteristics and distribution in beagles fed strontium-90.

A total of 66 primary bone sarcomas were diagnosed in 47 beagles; 43 of these dogs were part of the 403 beagles fed 90Sr and 4 were part of the 162 controls. Multiple primary bone sarcomas were found in 15 of the 47 beagles (32%). The incidence of multiple primary bone sarcoma was restricted to the two highest dose groups, except for a single control dog which developed two bone sarcomas. A threshold-like radiation dose response was observed; no sarcomas were observed in the lowest three dose groups, but the number of primary bone sarcomas increased rapidly in the higher dose groups. Of the 66 primary sarcomas, 49 were osteosarcomas (74%). As the dose increased, the proportion of osteosarcomas increased sharply, 4/10 (40%), 26/29 (90%), and 16/18 (89%), in the three highest dose groups. Thirteen of the bone sarcomas of other types occurred in males, and 4 in females, whereas 21 osteosarcomas occurred in males, and 28 in females. The ratio of bone sarcomas of the appendicular skeleton to those in the axial skeleton was 40:26, with osteosarcomas occurring more often in the appendicular than the axial skeleton (32:17), whereas nonosteogenic tumors showed no predilection (8:9). A statistical study of the distribution of bone sarcomas among 16 separate bone groups showed a correlation only with the distribution of cancellous bone volume-to-surface ratio and not with either skeletal mass distribution or dose distribution. The highest occurrence of sarcomas was in the humeri, femora, and mandible, and no occurrence in the coccygeal vertebrae, paws, or sternum. It is postulated that the distribution of bone sarcomas reflects a critical combination of the osteosarcoma precursor cell population, their cell division rate, and the radiation dose absorbed by these cells.

Genotoxicity of the phosphoramidate agent tabun (GA).

Five mutagenicity tests were performed on Agent GA (Tabun, phosphoramidocyanidic acid, dimethyl-, ethyl ester) as part of a program to demilitarize chemical warfare agents. GA was mutagenic in Salmonella spp. assays with S-9 and it was a direct-acting mutagen to mouse lymphoma cells. GA did not promote unscheduled DNA synthesis in rat hepatocytes; it induced sister chromatid exchanges in mouse cells in vitro but in vivo. The conclusion that GA is a weakly acting mutagen is supported by the fact that it was mutagenic in only three of the five assays, and that increases in mutagenicity were often less than 2-fold the controls and occurred near toxic levels.

Interspecies scaling of risk for radiation-induced bone cancer.

The induction of bone cancer in mice, dogs and humans, due to protracted alpha-irradiation from skeletal burdens of radium, was found to be represented by a single dose-rate/time/response function, when time was normalized with respect to species natural life-span. In the absence of other causes of death, the median time to death from bone cancer after 226Ra intake is given by tm* = 790-d*-0.29, based on the dog data, with -d* the time-weighted average absorbed dose rate in cGy/mLSF to skeleton and where time is measured as milli-life-span-fraction. On the basis of life-span scaling of the time dimension, data on cancer induction from studies with laboratory animals can be scaled to estimate human risks in a three-step process involving a three-dimensional analysis. The overall cancer risk distribution is shown to be a mountain-like surface rising from a Euclidean plane formed by the dose rate and survival time co-ordinates. At lower dose rates the time required for cancer induction may exceed the natural life-span yielding a quasi-threshold for cancer risk. For intakes of 226Ra in young adults this quasi-threshold is predicted to occur at a cumulative life-time alpha-radiation dose to the skeleton of about 1 Gy.

Fairness and rationing implications of medical necessity decisions.

When healthcare coverage entails medical necessity review, patients, providers, payers, and government agencies must confront issues of fairness and rationing. To explore the ethical ramifications of medical necessity decisions, we provide 2 illustrative case. In the first case, we discuss the implications of rule-based rationing and in the second we consider the influence of a medical group's internal review council on decisions of medical necessity. Both case examples illustrate why there are no agreed-on rules for setting a threshold for approving or denying care based on medical necessity and suggest that more complex medical cases require a more complex review process.

Time and dose-response study of the effects of vanadate on rats: morphological and biochemical changes in organs.

Vanadate at a dosage level of 0.9 mg V/kg per day produced acute toxic signs in rats when injected subcutaneously for 16 days. These signs were weakness, loss of appetite, dehydration, significant reduction in body weight, nose bleeding, and death. The pathological and biochemical changes were most severe in kidney tissue. The kidney lesions were bilateral and multifocal. At two days, degenerative and necrotic changes of the tubular and glomerular epithelium, thickening of glomerular membrane, vascular congestion, and edema were observed. At five days, proliferation of tubular epithelial and interstitial cells was observed. At 12 days, the cellular proliferation in both cortex and medulla was significantly greater. Fibrosis was observed at glomerular tuft, preglomeruli, pretubules, and interstitium (cortex and medulla). At 25 days, the collagen deposition reached the highest level in all regions, cellular proliferation decreased, and thickening of the arteriolar wall became prominent. The renal lesions were coupled with changes in the levels of protein, RNA, DNA, and hydroxyproline. At 40 days, the kidney showed signs of recovery. Blood urea nitrogen levels were significantly elevated at 2-25 days post-treatment. Stained tissue sections from liver, lung, heart, spleen, thymus, lymph nodes, testes, and adrenal glands of the treated rats were examined microscopically and appeared normal. Biochemically, significant changes (p less than .05) in protein, RNA, DNA, and hydroxyproline were also observed in these organs. At lower dosage (0.6 mg V/kg per day for 16 days), similar but less severe pathological and biochemical changes in kidneys and other organs were observed. At 0.3 mg V/kg per day for 16 days, the changes in the tissues were detected only at the biochemical level. These results indicate that the toxic effects of vanadium are cumulative and that vanadium-produced fibrosis in tissues is dose-dependent.

The lymphotoxic action of vanadate.

The acute toxicity of ammonium metavanadate (15.5 mg/kg) in mice was investigated to examine the induction of lymphoid necrosis to (1) verify the reproducibility of the lesions in the thymus, lymph nodes, and spleen; (2) determine whether the necrosis of lymphoid tissue previously observed during the first 3 days post-treatment but absent at 14 days was the result of differences in sensitivity of the mice or the result of recovery from the effects of vanadium; and (3) determine whether differences in the presence and the degree of necrosis between thymus and spleen were correlated with differences in the uptake of vanadium in these tissues. A timed sacrificed study was conducted in conjunction with a 48V tracer. In this study, BALB/C mice were injected subcutaneously (s.c.) with ammonium metavanadate solution (15.5 mg/kg). Groups of mice were sacrificed at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 21, and 28 days postexposure. Lymphoid necrosis was found in the thymus, spleen, lymph nodes, and bone marrow, with the necrosis being most severe in the thymus. The necrosis was moderate at 0.5 days, most severe at 2 to 3 days, with recovery beginning at 4 days, and proceeding to full recovery at 14 to 28 days. At 0.5 days post-treatment, the concentration of vanadium in thymus and spleen was 4.4 and 8.3 micrograms/g, respectively. At all post-treatment periods, with the exception of the 1- and the 4-day periods, the concentration of vanadium in spleen was significantly higher than in the thymus, p less than 0.05. The treated animals showed neurological signs (ataxia, convulsion, dyspnea, and paralysis of hind legs) between 5 min and 54 hr post-treatment, but the concentration of vanadium in the brain was very low during this period (less than 5.2% of blood concentration).