Clinical Briefs in Primary Care
Source: Abanses JC, et al. Vicks VapoRub induces mucin secretion, decreases ciliary beat frequency, and increases tracheal mucus transport in the ferret trachea. Chest 2009;135:143-148.
Those of us in the baby-boomer generation may recall in the 1940s-50s the application of a generous quantity of some Vicks® VapoRub-type salve (VvR) to the chest wall as a time-honored remedy that grandma suggested for the common cold. Toxicity of VvR, rather than efficacy, was the subject of this publication.
As with essentially any therapeutic agent, there is always the potential for adverse effects. Based upon a single case report of a toddler who developed respiratory distress subsequent to peri-nasal application of VvR, Abanses et al investigated potential adverse physiologic effects of VvR by experiments in ferrets.
VvR resulted in increased mucin secretion and decreased ciliary beat frequency (as observed by video micro-scopy), the combination of which could lead to small-airway obstruction. The authors report upon studies of menthol (an ingredient of VvR) in adults, in which, despite a decrease in nasal airflow, subjects universally report improved nasal symptoms; this change is attributed to the cooling effect of menthol in the nasal passages, which the brain interprets as increased airflow across the nostrils.
VvR appears to be a generally safe remedy, but case reports suggest caution in young children. The case presented here was initially treated as asthma; clinicians might consider asking about VvR use in children who present with new, otherwise unexplained symptoms of respiratory distress.
Prostate Cancer Risk with Testosterone Replacement
Source: Shabsigh R, et al. Testosterone therapy in hypogonadal men and potential prostate cancer risk: A systematic review. Int J Impot Res 2009;21:9-23.
Growth and development of the prostate is recognized to be testosterone (TST)-dependent. Clinicians have long held concerns that TST therapy might not only worsen symptoms of benign prostatic hyperplasia (BPH), but also stimulate the development, growth, proliferation, or aggressiveness of prostate cancer (PCa). Some of this concern stems logically from the observation that TST deprivation has salutary effects on prostate cancer growth.
This systematic review of 44 articles using FDA-approved agents was unable to directly provide a definitive answer to the question of whether TST replacement increases risk of PCa, but provides other interesting insights. First, trials of hypogonadal men treated with TST have not evidenced an increased risk for PCa; if anything, a protective effect may occur. Second, TST-treated men with a history of PCa did not experience more recurrences or metastases. Third, TST did not appear to influence Gleason scores when PCa was detected.
The authors conclude, "There is no evidence that TST increases risk of prostate cancer in hypogonadal men." Of some concern, however, are the case reports of aggressive PCa in recipients of a non-FDA-approved supplement containing TST, estradiol, chrysin, and elk velvet antler.
The Suicidal Process: Time to Intervene?
Source: Deisenhammer EA, et al. The duration of the suicidal process. J Clin Psychiatry 2009;70:19-24.
Suicide has been in the top causes of death in the United States for more than 20 years, usually ranking among the top 10. Clinicians would like to play a useful role in suicide prevention, yet data are sparse to inform about the interval between first suicidal ideation and a suicide attempt. Deisenhammer et al attempted to bridge this knowledge gap with a study of persons with failed suicide attempts, all of whom (n = 82) were interviewed within 72 hours of attempted suicide.
Most (83%) subjects were alone at the time of suicide conceptualization, and almost half reported the time from first suicide conception to attempt was 10 min or less. Nonetheless, during this brief interval, most (77%) had some contact (usually by telephone) with friends or family, and the majority indicated their wish to die or (according to their subjective reports) hinted at their death wish.
Interviews with subjects did not provide any insight as to what might have deterred the suicide attempt. Nonetheless, the fact that most suicidal subjects did make contact with others leaves open the possibility that some component of interpersonal communication has the potential to change the course of suicide attempts.
BNP to Guide Treatment of Heart Failure
Source: Pfisterer M, et al. BNP-guided vs symptom-guided heart failure therapy. JAMA 2009;301:383-392.
For Americans aged 65 or older, congestive heart failure (CHF) remains the most common diagnosis for hospital admission. Despite advances in therapy, the outcome of CHF remains daunting, with 5-year mortality rates as high as many malignancies. Because brain natriuretic peptide (BNP) reflects left ventricular wall stress, it can be useful to assist in diagnosis of CHF. Additionally, some, but not all, clinical trials have suggested that intensification of therapy to achieve optimization of BNP is associated with improved outcomes. The Trial of Intensified vs Standard Medical Therapy in Elderly Patients with Congestive Heart Failure (TIME-CHF) was devised to provide a more definitive comparison between the success of treatment intensification based upon symptoms vs level of BNP.
Patients with CHF (n = 499) were randomized to BNP-directed management (titrate treatment until BNP < 400 ng/mL) vs symptomatic management (intensify treatment until NYHA class II symptoms or better). Follow-up for the primary endpoint—hospitalization-free survival—was 18 months.
The BNP group experienced more aldosterone antagonists use, as well as more frequent increases in dose and utilization of ACE inhibitors and ARBs. However, there was no difference in the primary endpoint. In subjects age < 75 years, there was a reduction in mortality favoring BNP-directed management; however, because this was a secondary endpoint and the primary endpoint did not achieve statistical significance, it must be considered exploratory, not established. BNP-guided intensification of treatment is no more effective than standard symptom-directed methods.
Clopidogrel and CV Events: One Size Does NOT Fit All
Source: Simon T, et al. Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med 2009;360:363-375.
Utilization of clopidogrel (CPG) in patients with acute coronary syndromes (ACS is well established. Similarly, long-term prophylaxis with CPG for secondary prevention of CV events is evidence-based: The CAPRIE trial indicated that CPG is marginally superior to aspirin for endpoint reduction, and the PROFESS trial demonstrated that ER-dipyridamole/aspirin (Aggrenox®) failed to meet the non-inferiority threshold when compared to CPG for stroke prevention.
Residual risk in persons receiving CPG remains substantial, suggesting that perhaps the efficacy of CPG is not universal; i.e., some subjects might metabolize CPG differently than others, leading to different levels of efficacy (or adverse effects).
The French Registry of Acute ST-Elevation and Non-ST-Elevation Myocardial Infarction (FAST-MI) study enrolled ACS patients on CPG, and studied the relationship of genetic variants that result in variations in absorption, activation, and biologic activity of CPG. Next, the relationship between these genetic variants and adverse outcomes (death, stroke, MI) were studied.
The most important genetic variant appeared to be at the P450 2C19 gene. Those with 2 loss-of-function 2C19 genes were almost 4 times as likely to have a CV event over the next year as those without. The P450 2C19 gene is utilized for metabolism of CPG to its active metabolite; lesser antiplatelet activity would be anticipated in persons with impaired P450 2C19 activity. These results support the findings of another trial in the same issue of The New England Journal of Medicine that identified increased CV risk in persons with reduced 2C19 P450 functionality.
Estrogen + Progesterone and Breast Cancer
Source: Chlebowski RT, et al. Breast cancer after use of estrogen plus progestin in postmenopausal women. N Engl J Med 2009;360:573-587.
The Women's Health Initiative (WHI) provided convincing evidence that the use of estrogen + progesterone (E+P) in postmenopausal women is associated with an increased risk of breast cancer (BrCa). The outcomes of this clinical trial motivated large numbers of women and their clinicians to rethink the risk-benefit balance of hormone therapy (HT), evoking a sea-change in prescribing habits.
Despite the acknowledged association between E+P and BrCa in WHI, a concomitant decline in use of mammography following the WHI news invited the possibility that post-WHI, less BrCa screening might have influenced the observed BrCa decline rather than simply less E+P use. To study this issue, WHI investigators evaluated two data sets: the original WHI population (n = 16,608 women without BrCa at baseline) and a second observational study population (n = 41,449 without BrCa at baseline). The observational study group did not receive advice about whether to use E+P, but were informed about the results of the interventional WHI when it became available. In the observational WHI population, more than 16,000 women were taking E+P at baseline.
Long-term follow-up of the observational WHI population showed an increased incidence of BrCa in women who had used E+P. BrCa incidence in this population declined subsequent to HT discontinuation. This suggests the possibility that some early breast cancers may regress or disappear if HT is stopped. The data did not, however, provide a meaningful association between lesser use of mammography and reduced BrCa.VapoRub Revisited; Prostate Cancer Risk with Testosterone Replacement; The Suicidal Process: Time to Intervene?; BNP to Guide Treatment of Heart Failure; Clopidogrel and CV Events: One Size Does NOT Fit All; Estrogen + Progesterone and Breast Cancer;
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