Risks and Benefits of an Extended 10-year Tamoxifen Regimen for Breast Cancer
Source: Davies C, et al. Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of estrogen receptor-positive breast cancer: ATLAS, a randomised trial. Lancet 2013;381:805-816.
The prevailing 5-year tamoxifen regimen for breast cancer has been shown to reduce breast cancer mortality by as much as one-third over a 15-year interval; a comparison with a shorter regimen (1-2 year) found the longer duration to be superior. Would even longer tamoxifen administration (i.e., > 5 years) provide even greater risk reduction of breast cancer and its consequences, and if so, would longer regimens induce greater toxicity to other non-targeted tissues (e.g., induction of endometrial cancer)?
The Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) trial randomized women with estrogen receptor-positive breast cancer (B-CA) to either 5 years (n = 3418) or 10 years (n = 3428) of tamoxifen. Follow-up continued for 5 years after conclusion of the 10-year tamoxifen course. The estrogen-receptor positive B-CA group actually represents only about half of all of the women enrolled in ATLAS; the estrogen-receptor negative population of ATLAS demonstrated no risk reduction through longer tamoxifen administration.
Numerous outcomes favored 10-year tamoxifen over 5 years and were statistically significant: B-CA recurrence (617 vs 711 cases), B-CA mortality (639 vs 722 deaths), and ischemic heart disease death or hospitalization (127 vs 163 cases). On the negative side of the equation, all-cause mortality was not impacted by the longer tamoxifen regimen, and there was a significant increase in pulmonary embolism (41 vs 21 cases) as well as endometrial cancers (116 cases vs 63 cases).
These results were apparently sufficiently impressive enough to make the cover story in the Lancet. Your reviewer, however, takes pause at the fact that similar to the situation with results for prostate cancer screening, which has recently been diminished by convincing evidence that screening may reduce prostate cancer mortality but not total mortality a 10-year tamoxifen regimen reduces B-CA mortality but not total mortality, and has not-insubstantial adverse effects as well as costs.
Is There More Pro than Con in Probiotics in Critically Ill Adults?
Source: Barraud D, et al. Impact of the administration of probiotics on mortality in critically ill adult patients. Chest 2013; 143:646-655.
The technical definition of probiotic offered by the World Health Organization and the Food and Agriculture Organization sounds promising enough: "viable microorganisms that, when ingested in a sufficient amount, can be beneficial for health." Unfortunately, the existing literature on the benefits of probiotics is not quite so convincing.
Barraud et al performed a meta-analysis of randomized, controlled trials published between 1950-2012 in which probiotics were used in the intensive care unit (ICU) setting, ultimately netting 13 clinical trials, all published after 2002 (n = 1439). The probiotic used in each of these trials was in the Lactobacillus family, and although some trials used only one Lactobacillus strain, several trials used mixed strains of Lactobacilli. Endpoints included ICU mortality, hospital mortality, ICU infections, incidence of diarrhea, and duration of mechanical ventilation.
Of the above-mentioned endpoints, a statistically significant favorable odds ratio was seen only for the incidence of ICU-acquired pneumonia, even though the overall larger category of ICU-acquired infections was not statistically significantly improved. Although the failure to achieve significance to numerous endpoints is disconcerting, the authors point out that since probiotic administration is generally safe, the favorable impact on ICU-acquired pneumonia (a reduction of approximately 40%) might prompt consideration for use in patients known to be particularly at risk for this consequence.
Are OSA Outcomes Better in the Hands of Sleep Specialists than Primary Care Clinicians?
Source: Chai-Coetzer CL, et al. Primary care vs specialist sleep center management of obstructive sleep apnea and daytime sleepiness and quality of life: A randomized trial. JAMA 2013;309:997-1004.
The recognition of obstructive sleep apnea (OSA) as a health burden of compelling epidemiologic presence with significant impact on both quality of life and cardiovascular health has been recognized by health care providers of essentially all disciplines. Increasingly, sophisticated sleep laboratory monitoring devices allow ever more detailed (and usually more costly) understanding of sleep dysregulation. At the same time, awareness of the frequency and consequences of OSA among diverse disciplines of medicine has resulted in a sufficiently burgeoning population of individuals who merit screening that sleep labs are often unable to keep pace with the increasing demand.
A proliferation of simpler, home-based tools for the identification and potential management of OSA that can be used by sleep specialists and primary care clinicians alike has prompted the question of whether outcomes for OSA patients attended by sleep specialists (who are usually not primary care clinicians), typically with complex sleep analysis tools (which are most commonly employed in a specific sleep laboratory), are superior to outcomes for patients attended by primary care clinicians with less sophisticated home-based tools.
The authors report on a randomized, controlled, non-inferiority trial of patients with OSA identified and treated either in a university sleep laboratory by sleep specialists or by community primary care practices. The primary outcome was improvement in the Epworth Sleepiness Scale, a commonly used and validated scoring system for monitoring sleepiness associated with OSA.
At the end of the 6-month trial, scores on the Epworth Sleepiness Scales were identical in both groups, and outcomes in the primary care group were determined to be non-inferior to sleep specialist care. Hopefully, primary care clinicians will become more involved in the identification and management of OSA, since equally salutary outcomes are seen in their hands as in the hands of sleep specialists.
Inhaled Steroids Increase Risk of TB in COPD Patients
Source: Kim J, et al. Inhaled corticosteroid is associated with an increased risk of TB in patients with COPD. Chest 2013; 143:1018-1024.
Reactivation of tuberculosis (tb) is an ongoing concern among patients who receive immunosuppressive agents such as TNF-alpha agents for rheumatoid arthritis. Similarly, long-term use of systemic steroids (i.e., ≥ 30 days) in amounts as small as 7.5 mg/day of prednisone increases the risk of TB. Inhaled corticosteroids (ICS) have been associated with systemic effects such as growth retardation (in asthma), reduced bone mineral density, and increased risk of pneumonia (in chronic obstructive pulmonary disease [COPD]). Whether ICS might also be associated with risk for development or reactivation of TB has not been fully clarified.
Kim et al performed a retrospective analysis of COPD patients (n = 620) in a university hospital in South Korea (where the background prevalence of TB is substantially greater than many other nations) to compare the rate of TB activation in persons who had received ICS with controls. To eliminate the confounding factor of systemic steroid use, COPD patients who had received ≥ 7.5 mg for 1 month or more were excluded from the analysis.
There was a substantially greater and statistically significant risk for development of active TB among COPD patients who had been treated with ICS (hazard ratio = 9). In patients whose baseline chest x-ray showed evidence of prior (but quiescent) TB, the hazard ratio for activation of TB was 25!
Although the prevalence of TB is much greater in Korea than in the United States, these data suggest greater vigilance for TB activation in patients chronically using ICS, especially if their x-rays indicate evidence of prior TB.
The ASH Position Paper on Orthostatic Hypotension
Source: Shibao C, et al. ASH position paper: Evaluation and treatment of orthostatic hypotension. J Clin Hypertens 2013;15:147-153.
Standing from a seated or supine position is normally associated with minimal, if any, blood pressure (BP) change, thanks to homeostatic mechanisms that alter splanchnic and peripheral blood compartments by selective intravascular redistribution and vascular tone. When BP change upon standing exceeds 20/10 mmHg, a diagnosis of orthostatic hypotension (OH) is established. Although tilt-table testing is often suggested for formal diagnosis, simple office measurement of BP 1-3 minutes after standing suffices.
Although sometimes OH produces minor distracting symptoms of dizziness that may be diminished by standing slowly, leg crossing, maintenance of good fluid balance, etc., it can also be a cause of falls, with anticipatable subsequent catastrophes such as hip fracture. Additionally, OH epidemiological data have noted an association between OH and stroke.
A variety of commonly used medications can precipitate or exacerbate OH, including alpha blockers, diuretics, vasodilators, dopamine agonists, and tricyclic antidepressants, modulation of which may improve OH symptoms. Pharmacologic treatments for OH include fludrocortisone (to increase intravascular volume), midodrine (a short-acting vasopressor agent), and other sympathomimetic agents.
OH is also seen in several primary neurologic disorders such as Parkinson's disease, multiple system atrophy, and Lewy body dementia.
Clinicians should suspect OH particularly in patients who report dizziness, unexplained falls, or syncope, although even symptoms such as blurred vision or neck/shoulder pain ("coat hanger" distribution pain) may reflect OH. Fortunately, a variety of lifestyle and pharmacologic treatments can be helpful.