Use of angiotensin-converting enzyme inhibitor therapy and dose-related outcomes in older adults with new heart failure in the community

OBJECTIVE: To evaluate the dose-related benefit of angiotensin-converting enzyme (ACE) inhibitor therapy among older adults with heart failure and to evaluate whether low-dose ACE inhibitor therapy is better than none. DESIGN: Observational cohort study. SETTING: Community-dwelling older adults in Ontario, Canada. PATIENTS/PARTICIPANTS: We identified 16539 adults 66 years or older who survived 45 days following their first heart failure hospitalization discharge. MEASUREMENT AND MAIN RESULTS: Multivariate techniques including propensity scores were used to study the association between the dose of ACE inhibitor therapy dispensed and 3 outcomes: survival, survival or heart failure rehospitalization, and survival or all-cause hospitalization at 1 year of follow-up. Logistic regression models explored the association between initial dose dispensed and subsequent dose reduction or drug cessation. Overall, 10793 (65.3%) of patients were dispensed ACE inhibitor therapy, with more than a third (3935; 36.5%) initiated on low-dose therapy. Relative to dispensing of low-dose ACE inhibitor therapy, nonuse was associated with increased mortality (hazard ratio [HR], 1.12; 95% confidence interval [CI], 1.02 to 1.22). Dispensing medium-dose therapy provided a benefit similar to low-dose (HR, 0.94; CI, 0.86 to 1.03) and dispensing of high-dose therapy was associated with improved survival benefit (HR, 0.76; CI, 0.68 to 0.85). Relative to dispensing of low-dose ACE inhibitor therapy, dispensing high-dose conferred a benefit (HR, 0.87; CI, 0.80 to 0.95) on the composite outcome of 1-year mortality or heart failure hospitalization and the composite outcome of 1-year mortality or all-cause hospitalization (HR, 0.87; CI, 0.81 to 0.93). Relative to those dispensed low-dose ACE inhibitor therapy, those initially dispensed high-dose therapy were twice as likely to have their subsequent dose reduced or the therapy discontinued (odds ratio, 2.36; CI, 2.07 to 2.69). CONCLUSION: Our findings suggest that when possible, older adults should be titrated to the higher doses of ACE inhibitor therapy evaluated in clinical trials. If older adults cannot tolerate higher doses, then low-dose ACE inhibitor therapy is superior to none. High-dose ACE inhibitor therapy is not as well tolerated as lower doses.     

Liver dysfunction in Pennsylvania's multitransfused hemophiliacs

Transaminase values [alanine amino transferase (ALT) and aspartate amino transferase (AST)] and markers for hepatitis B were serially determined in 558 hemophiliacs exposed to blood products. Hepatitis B surface antigen (HB_sAg) persistent for over 12 months was present in 6% of the patients. Antibody to hepatitis B surface antigen (anti-HBs) was noted in 90% of the 259 patients treated with factor VIII or IX concentrates but in only 49% of the 43 patients treated with fresh frozen plasma (FFP) or cryoprecipitate. Persistently abnormal transaminase values were noted in 31% of the patients treated with commercial concentrates but in only one (2%) of the patients exposed to cryoprecipitate or FFP. This difference continued even when the two groups of patients were matched for the amount of blood products, up to 50, 000 units, which they had received in the study period. In the concentrate-treated patients, no correlation could be found between transaminase values and the number of units of factor VIII or IX they had received during the six years of the study (1973–1978).Supported in part by the Pennsylvania Hemophilia Centers and the Pennsylvania State-Wide Hemophilia Program.     

Differences in presentation and follow-up between HIV-1 antibody positive teenagers and adults: the need for a more focused approach to care?

Our findings show a high rate of loss to follow-up in HIV-positive teenagers compared with adults. Of concern is the fact that this group also have high rates of sexually transmitted infections, unprotected sex and pregnancy. There is an urgent need to examine the reasons for this and adopt strategies to minimize risk-taking behaviour and to improve access to appropriate healthcare.     

Treatment strategies for central nervous system infections: an update

Introduction: Central nervous system infection continues to be an important cause of mortality and morbidity worldwide. Our incomplete knowledge on the pathogenesis of how meningitis-causing pathogens cause CNS infection and emergence of antimicrobial resistance has contributed to the mortality and morbidity. An early empiric antibiotic treatment is critical for the management of patients with bacterial meningitis, but early recognition of bacterial meningitis continues to be a challenge.

Areas covered: This review gives an overview on current therapeutic strategies for CNS infection with a focus on recent literature since 2010 on bacterial meningitis. Bacterial meningitis is a medical emergency, requiring early recognition and treatment. The selection of appropriate empiric antimicrobial regimen, after incorporating the epidemiology of bacterial meningitis, impact of vaccination, emergence of antimicrobial-resistant bacteria, role of adjunctive therapy and the current knowledge on the pathogenesis of meningitis and associated neuronal injury are covered.

Expert opinion: Prompt treatment of bacterial meningitis with an appropriate antibiotic is essential. Optimal antimicrobial treatment of bacterial meningitis requires bactericidal agents able to penetrate the blood–brain barrier, with efficacy in cerebrospinal fluid. Emergence of CNS-infecting pathogens with resistance to conventional antibiotics has been increasingly recognized, but development of new antibiotics has been limited. More complete understanding of the microbial and host factors that are involved in the pathogenesis of bacterial meningitis and associated neurologic sequelae is likely to help in developing new strategies for the prevention and therapy of bacterial meningitis.     

Differential changes in alpha- and beta-adrenoceptor linked [45Ca2+] uptake in platelets from patients with anorexia nervosa.

[45Ca2+] Uptake was studied in response to adrenaline, isoprenaline, noradrenaline, and (Bu)2cAMP in platelets from patients with anorexia nervosa. In both controls and anorectics, adrenaline, isoprenaline, noradrenaline, and (Bu)2cAMP stimulated [45Ca2+] uptake. In receptor subtype characterisation studies on control platelets, adrenaline-stimulated [45Ca2+] uptake was blocked by yohimbine (an alpha 2-adrenoceptor antagonist) and the specific beta 2-adrenoceptor antagonist ICI 118,551, but not by atenolol (a beta 1-antagonist). Isoprenaline action was blocked by ICI 118,551, but not by yohimbine. Noradrenaline-stimulated [45Ca2+] uptake was blocked by yohimbine but not by ICI 118,551. In platelets from anorectic patients, there was a significant increase in noradrenaline-stimulated [45Ca2+] uptake, a significant diminution in adrenaline and isoprenaline-stimulated [45Ca2+] uptake, but no significant difference in (Bu)2cAMP-stimulated [45Ca2+] uptake, when compared with controls. Basal uptake was also significantly enhanced in anorectics and was found to be inhibited with verapamil but not adrenoceptor antagonist. These data firstly indicate that both alpha 2- and beta 2-adrenoceptor activation elicits [45Ca2+] uptake by platelets. It is proposed that this stimulated [45Ca2+] uptake does not reflect changes in cytosolic Ca2+ but to localized changes of Ca2+ at the plasma membrane, possibly associated with receptor activation, per se. The respective increase and decrease of alpha- and beta-adrenoceptor activity in platelets from anorectic patients is in accord with other reports of changes of adrenoceptor number and type in platelets and other cells from anorectic patients. There may also be an increase in calcium channel activity in platelets from anorectics.     

Angiotensin stimulation of bovine adrenocortical cell growth.

Factors controlling proliferation of adrenocortical cells have been studied in monolayer cultures of bovine adrenocortical cells. Angiotensin II stimulated cell proliferation and [3H]thymidine incorporation into DNA with a half-maximal effective concentration of 0.96 +/- 0.27 nM. Similar sensitivity to angiotensin III with reduced sensitivity to angiotensin I and tetradecapeptide renin substrate was observed. Although sensitivity to angiotensin II was equivalent to that for fibroblast growth factor (1.5 nM half-maximal effective concentration), maximal effects of angiotensin were less than for fibroblast growth factor and serum. High concentrations of insulin (1-10 micrometer) also stimulated [3H]thymidine incorporation into DNA and cell proliferation. [Sar1,Ile5,Ile8]Angiotensin II, a competitive antagonist of angiotensin II, blocked angiotensin II stimulation of DNA synthesis but did not affect fibroblast growth factor and insulin stimulation of DNA synthesis. Corticotropin (ACTH) blocked the stimulatory effects of both angiotensin II and fibroblast growth factor. The dose-response curves for angiotensin II stimulation of steroidogenesis were similar to those for stimulation of [3H]thymidine incorporation into DNA. Among the seven cell types examined, only adrenocortical cells responded to angiotension II with stimulation of DNA synthesis.     

The influence of an intense cardiovascular disease risk factor modification program

In an effort to make intensive lifestyle modification programs more accessible to patients with cardiovascular disease, the Ornish Program was offered at eight independent medical centers located across the United States. The purpose of this study was to determine if one of these independent sites was able to replicate outcomes produced by the original Ornish Program. Fifty program participants from six different cohorts provided baseline, 3- and 12-month data consisting of blood lipids, body fat, blood pressure, anginal pain, quality of life, stress, depression, social support, and hostility. A pooled analysis showed significant reductions in almost all physiological and psychosocial variables with most reductions persisting for at least 12 months. These findings suggest that cardiovascular disease patients who choose to participate in an independent, intensive lifestyle modification program can experience significant improvements in both physiological and psychosocial cardiovascular disease risk factors.