Subgroup analyses to determine cardiovascular risk associated with nonsteroidal antiinflammatory drugs and coxibs in specific patient groups

OBJECTIVE: To explore the extent to which clinical characteristics influence the association between cyclooxygenase 2 inhibitors (coxibs) and/or nonselective nonsteroidal antiinflammatory drugs (NSAIDs) and increased cardiovascular disease (CVD) risk in specific patient subgroups. There is substantial concern regarding the potential cardiovascular adverse effects of selective coxibs and nonselective NSAIDs, but many patients with arthritis experience important clinical benefits from these agents. METHODS: The study population consisted of Medicare beneficiaries also eligible for a drug benefits program for older adults during the years 1999-2004. We calculated the relative risk (RR) for CVD events (myocardial infarction [MI], stroke, congestive heart failure, and cardiovascular death) among users of coxibs or nonselective NSAIDs in the prior 6 months compared with nonusers. We assessed biologic interaction between these medication exposures and important patient characteristics. RESULTS: In the primary cohort, we identified 76,082 new users of coxibs, 53,014 new users of nonselective NSAIDs, and 46,558 nonusers. Compared with nonusers, the adjusted RR of CVD events for new users of each agent increased for rofecoxib (RR 1.22, 95% confidence interval [95% CI] 1.14, 1.30) and decreased for naproxen (RR 0.79, 95% CI 0.67, 0.93). Several patient characteristics were found to increase the risk of CVD events among users of some agents in both the primary and secondary cohorts, including age >/=80 years, hypertension, prior MI, prior CVD, rheumatoid arthritis, chronic renal disease, and chronic obstructive pulmonary disease. Rofecoxib and ibuprofen appeared to confer an increased risk in multiple patient subgroups. CONCLUSION: Many nonselective NSAIDs and coxibs are not associated with an increased risk of CVD events. However, several patient characteristics identify important subgroups that may be at an increased risk when using specific agents.     

Methods of investigation for cardiac autonomic dysfunction in human research studies

This consensus document provides evidence‐based guidelines regarding the evaluation of diabetic cardiovascular autonomic neuropathy (CAN) for human research studies; the guidelines are the result of the work of the CAN Subcommittee of the Toronto Diabetic Neuropathy Expert Group. The subcommittee critically reviewed the limitations and strengths of the available diagnostic approaches for CAN and the need for developing new tests for autonomic function. It was concluded that the most sensitive and specific approaches currently available to evaluate CAN in clinical research are: (1) heart rate variability, (2) baroreflex sensitivity, (3) muscle sympathetic nerve activity, (4) plasma catecholamines, and (5) heart sympathetic imaging. It was also recommended that efforts should be undertaken to develop new non‐invasive and safe CAN tests to be used in clinical research, with higher sensitivity and specificity, for studying the pathophysiology of CAN and evaluating new therapeutic approaches. Copyright © 2011 John Wiley & Sons, Ltd.     

Ethnic variation in certain hematological and biochemical reference intervals in a south Indian healthy adult population

BACKGROUND: We established the biochemical and hematological reference intervals among a south Indian healthy adult population attending an HIV referral centre in Chennai, southern India. METHODS: In a cross sectional study, 213 study subjects (129 male and 84 female) were studied between March and August 2005. All of the parameters were analyzed using standard hematological and biochemical techniques. RESULTS: Certain biochemical (viz. total bilirubin, alanine transaminase, albumin, creatinine, total protein, lipid profile, creatine phosphokinase, uric acid and lactate) and hematological (mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration and lymphocyte levels) parameters presented higher upper limits. In addition, the upper limits of white blood cell count, platelet count, hematocrit, red blood cell count and hemoglobin level were low in comparison to the currently reported ranges. CONCLUSION: Ethnic variation in reference intervals was observed in certain biochemical and hematological analytes in a south Indian adult population.     

Successful endoscopic ultrasound-guided overstenting biliary drainage through a pre-existing proximal migrated metal biliary stent

Biliary endoscopic drainage using metallic self-expanded stents has become a well-established method for palliative treatment of malignant biliary obstruction. However, its occlusion, mainly by tumor overgrowth, is still the main complication without a standard treatment. We here describe a new method of treatment for biliary metallic stent occlusion, through the echo guided biliary drainage. We present a 68-year-old patient with metastatic pancreatic cancer previously treated for jaundice with ERCP and self-expandable metallic stent insertion. Four weeks later, the patient developed jaundice and symptoms of gastric outlet obstruction. A new ERCP confirmed obstruction of the second portion of the duodenum, due to diffuse tumor growth. EUS was performed, and the previous metal biliary stent was seen occluded at the distal portion in the common bile duct. A EUS-guided choledocododenostomy was performed and then, an overlapping self-expanding metal enteral stent was placed through the malignant obstruction. There were no early complications and the procedure was also clinically effective in relieving jaundice and gastric outlet obstruction symptoms. If ERCP fails in the management of occluded biliary metallic stents, EUS biliary drain can provide effective biliary decompression and should be considered an alternative to other endoscopic techniques.     

Evaluation of the anti-diabetic properties of Mucuna pruriens seed extract

ObjectiveTo explore the antidiabetic properties of Mucuna pruriens(M. pruriens).MethodsDiabetes was induced in Wistar rats by single intravenous injection of 120 mg/kg of alloxan monohydrate and different doses of the extract were administered to diabetic rats. The blood glucose level was determined using a glucometer and results were compared with normal and untreated diabetic rats. The acute toxicity was also determined in albino mice.ResultsResults showed that the administration of 5, 10, 20, 30, 40, 50, and 100 mg/kg of the crude ethanolic extract of M. pruriens seeds to alloxan-induced diabetic rats (plasma glucose > 450 mg/dL) resulted in 18.6%, 24.9%, 30.8%, 41.4%, 49.7%, 53.1% and 55.4% reduction, respectively in blood glucose level of the diabetic rats after 8h of treatment while the administration of glibenclamide (5 mg/kg/day) resulted in 59.7% reduction. Chronic administration of the extract resulted in a significant dose dependent reduction in the blood glucose level (P<0.001). It also showed that the antidiabetic activity of M. pruriens seeds resides in the methanolic and ethanolic fractions of the extract. Acute toxicity studies indicated that the extract was relatively safe at low doses, although some adverse reactions were observed at higher doses (8-32 mg/kg body weight), no death was recorded. Furthermore, oral administration of M. pruriens seed extract also significantly reduced the weight loss associated with diabetes.ConclusionsThe study clearly supports the traditional use of M. pruriens for the treatment of diabetes and indicates that the plant could be a good source of potent antidiabetic drug.     

Improved outcome with preventive cardiac resynchronization therapy in the elderly: a MADIT-CRT substudy

Preventive Cardiac Resynchronization in the Elderly. Background: Elderly patients comprise a large portion of patients with heart failure (HF). Limited data exist on the effectiveness of cardiac resynchronization therapy with defibrillator (CRT‐D) in patients with mild HF symptoms in this population. Methods and Results: The benefit of CRT‐D compared with ICD‐only therapy in reducing HF or death was assessed by age categories (prespecified as <60 [n = 548], 60–74 [n = 941], and ≥75 [n = 331] years) among 1,820 patients in MADIT‐CRT. In patients with ICD‐only, there was a graded age‐related increase in the Kaplan–Meier cumulative probability of HF or death at 3‐year follow‐up (19%, 33%, and 36%, in patients aged <60, 60–74, and ≥75 years, respectively, P = 0.003). Multivariate analysis demonstrated that CRT‐D therapy was associated with a significant reduction in the risks of HF or death in patients aged 60–74, and ≥75 years (HR = 0.57, P = <0.001 and HR = 0.59, P = 0.017, respectively), and no significant benefit in patients aged <60 years (HR = 0.81, P = 0.3; P‐value for all treatment‐by‐age interactions >0.10). There was no significant difference in the rate of device‐related adverse events within 90 days following CRT‐D implantation among age‐subgroups (16.7%, 15.7%, and 11.7%, in patients <60, 60–74, and ≥75 years, respectively, P = 0.42) . Conclusion: CRT‐D was associated with a significant clinical benefit in older patients (≥60 years) during an average 2.4‐year follow‐up. These effects were preserved for the elderly patients ≥75 years of age but attenuated in patients <60 years. Elderly patients had no increase in device‐related adverse events compared with younger patients . (J Cardiovasc Electrophysiol, Vol. 22, pp. 892‐897, August 2011)     

Systematic review and meta-analysis of methotrexate use and risk of cardiovascular disease

Inflammation predicts risk for cardiovascular disease (CVD) events, but the relation of drugs that directly target inflammation with CVD risk is not established. Methotrexate is a disease-modifying antirheumatic drug broadly used for the treatment of chronic inflammatory disorders. A systematic review and meta-analysis of evidence of relations of methotrexate with CVD occurrence were performed. Cohorts, case-control studies, and randomized trials were included if they reported associations between methotrexate and CVD risk. Inclusions and exclusions were independently adjudicated, and all data were extracted in duplicate. Pooled effects were calculated using inverse variance-weighted meta-analysis. Of 694 identified publications, 10 observational studies in which methotrexate was administered in patients with rheumatoid arthritis, psoriasis, or polyarthritis met the inclusion criteria. Methotrexate was associated with a 21% lower risk for total CVD (n = 10 studies, 95% confidence interval [CI] 0.73 to 0.87, p <0.001) and an 18% lower risk for myocardial infarction (n = 5, 95% CI 0.71 to 0.96, p = 0.01), without evidence for statistical between-study heterogeneity (p = 0.30 and p = 0.33, respectively). Among prespecified sources of heterogeneity explored, stronger associations were observed in studies that adjusted for underlying disease severity (relative risk 0.64, 95% CI 0.43 to 0.96, p <0.01) and for other concomitant medication (relative risk 0.73, 95% CI 0.63 to 0.84, p <0.001). Publication bias was potentially evident (funnel plot, Begg's test, p = 0.06); excluding studies with extreme risk estimates did not, however, alter results (relative risk 0.81, 95% CI 0.74 to 0.89). In conclusion, methotrexate use is associated with a lower risk for CVD in patients with chronic inflammation. These findings suggest that a direct treatment of inflammation may reduce CVD risk.     

Trajectories of Quality of Life in Older Persons with Advanced Illness

OBJECTIVES: To examine subjective ratings of quality of life (QoL) in older adults with advanced illness. DESIGN: Observational cohort study with interviews at least every 4 months for up to 2 years conducted between December 1999 and December 2002. SETTING: Participants' homes. PARTICIPANTS: One hundred eighty‐five community‐dwelling individuals aged 60 and older with advanced cancer, heart failure, or chronic obstructive pulmonary disease. MEASUREMENTS: Participants were asked how they would rate their overall QoL. RESULTS: Of participants who died, 46% reported good or best possible QoL at their final interview, 21% reported improvement in QoL from their penultimate to final interview, and 39% reported no change. Forty‐nine percent of participants reported two or more changes in the direction of their QoL trajectories (e.g., QoL improved then declined). As measured over time in a multivariable longitudinal regression analysis, greater activity of daily living disability (adjusted odds ratio (AOR)=0.85, 95% confidence interval (CI)=0.75–0.95) and depressed mood (AOR=0.42, 95%CI=0.27–0.66) were associated with poorer QoL, whereas better self‐rated health (AOR=4.79, 95% CI=2.99–7.69) and having grown closer to one's church (AOR=1.99, 95% CI=1.17–3.39) were associated with better QoL. CONCLUSION: Although declining QoL is not an inevitable consequence of advancing illness, individuals' ratings of QoL are highly variable over time, suggesting that temporary factors may influence subjective QoL. Functional status, depression, and connection to one's religious community are shared determinants of QoL.     

H2S mediates O2 sensing in the carotid body

Gaseous messengers, nitric oxide and carbon monoxide, have been implicated in O₂ sensing by the carotid body, a sensory organ that monitors arterial blood O₂ levels and stimulates breathing in response to hypoxia. We now show that hydrogen sulfide (H₂S) is a physiologic gasotransmitter of the carotid body, enhancing its sensory response to hypoxia. Glomus cells, the site of O₂ sensing in the carotid body, express cystathionine γ-lyase (CSE), an H₂S-generating enzyme, with hypoxia increasing H₂S generation in a stimulus-dependent manner. Mice with genetic deletion of CSE display severely impaired carotid body response and ventilatory stimulation to hypoxia, as well as a loss of hypoxia-evoked H₂S generation. Pharmacologic inhibition of CSE elicits a similar phenotype in mice and rats. Hypoxia-evoked H₂S generation in the carotid body seems to require interaction of CSE with hemeoxygenase-2, which generates carbon monoxide. CSE is also expressed in neonatal adrenal medullary chromaffin cells of rats and mice whose hypoxia-evoked catecholamine secretion is greatly attenuated by CSE inhibitors and in CSE knockout mice.     

EMS Providers and Exception from Informed Consent Research: Benefits, Ethics, and Community Consultation

Abstract Background. As attention to, and motivation for, emergency medical services (EMS)-related research continues to grow, particularly exception from informed consent (EFIC) research, it is important to understand the thoughts, beliefs, and experiences of EMS providers who are actively engaged in the research. Objective. We explored the attitudes, beliefs, and experiences of EMS providers regarding their involvement in prehospital emergency research, particularly EFIC research. Methods. Using a qualitative design, 24 participants were interviewed including nationally registered paramedics and Virginia-certified emergency medical technicians employed at Richmond Ambulance Authority, the participating EMS agency. At the time of our interviews, the EMS agency was involved in an EFIC trial. Transcribed interview data were coded and analyzed for themes. Findings were presented back to the EMS agency for validation. Results. Overall, there appeared to be support for prehospital emergency research. Participants viewed research as necessary for the advancement of the field of EMS. Improvement in patient care was identified as one of the most important benefits. A number of ethical considerations were identified: individual risk versus public good and consent. The EMS providers in our study were open to working with EMS researchers throughout the community consultation and public disclosure process. Conclusion. The EMS providers in our study valued research and were willing to participate in studies. Support for research was balanced with concerns and challenges regarding the role of providers in the research process.