Clinical Briefs

By Louis Kuritzky, MD, Clinical Assistant Professor, University of Florida, Gainesville. Dr. Kuritzky is an advisor for Endo, Kowa, Pricara, and Takeda.

Risks and Benefits of an Extended 10-year Tamoxifen Regimen for Breast Cancer

Source: Davies C, et al. 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. 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.


The ASH Position Paper on Orthostatic Hypotension

Source: Shibao C, et al. 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.

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.