Primecuts – This Week In The Journals

July 21, 2014

By Caroline A. Nelson, MD

Peer Reviewed

New legislation signed by Missouri Governor Jay Nixon has opened the door for medical school graduates to treat patients in underserved primary care settings without residency training or passing Step 3 of the United States Medical Licensing Examination[1]. After 30 days of supervision by a collaborating physician, the law would permit these new “Assistant Physicians” to treat patients with only indirect supervision as far as 50 miles away. The Missouri State Medical Association helped draft the law to provide an “outside the box…solution for rural healthcare access;” however, it is opposed by many groups including the American Medical Association. As we approach the 30-day milestone of intern year, how comfortable would we feel treating patients without direct supervision? With that question in mind, let’s begin this week’s Primecuts by turning to guidance from the New England Journal of Medicine.

Cholesterol levels are not the full story: Rethinking niacin for atherosclerotic vascular disease

Niacin has been prescribed since the 1950’s to reduce low-density lipoprotein (LDL) and increase high-density lipoprotein (HDL) cholesterol levels. Laropiprant, a selective antagonist of the prostaglandin D2 receptor subtype 1 (DP1), has been shown to decrease niacin’s well-known side effect of flushing[2]. In this study, 25,673 adults with vascular disease on statin-based, LDL cholesterol-lowering therapy were randomized to receive 2 g of extended-release niacin with 40 mg of laropiprant or matching placebo daily[3]. The primary outcome over a median follow-up period of 3.9 years was the first major vascular event (nonfatal myocardial infarction, death from coronary causes, stroke, or arterial revascularization). On average, the LDL and HDL levels of participants assigned to niacin-laropiprant were 10 mg per deciliter lower and 6 mg per deciliter higher than the levels in those assigned to placebo, respectively. No significant difference was observed, however, in the incidence of major vascular events (13.2% vs. 13.7% in each study group; rate ratio, 0.96; 95% confidence interval [CI], 0.90 to 1.03; P=0.29). Participants assigned to niacin-laropiprant did experience a statistically significant increase in serious disturbances in diabetes control, diabetes diagnoses, and serious adverse events associated with the gastrointestinal system, musculoskeletal system, skin, infection, and bleeding. Although niacin may be relevant for select high-risk patients, the risk-benefit profile in this study indicates that clinicians should prescribe with caution.

Primary androgen-deprivation therapy (ADT) may not prolong the lives of men with localized prostate cancer

A population-based cohort study published in JAMA Internal Medicine raises serious concern over the use of primary ADT in men with localized (T1/T2) prostate cancer[4]. The study analyzed data on 66,717 Medicare patients 66 years or older diagnosed with prostate cancer in United States geographical areas covered by the Surveillance, Epidemiology, and End Results Program between 1992 and 2009. The authors used instrumental variable analysis to compare overall and disease-specific survival between the top and bottom tertile areas in terms of primary ADT usage rates while controlling for potential biases associated with unmeasured confounding variables. Over a median follow-up of 110 months, primary ADT was not associated with improved 15-year overall or disease-specific survival following diagnosis. The 15-year overall survival rate was 15.9% vs. 16.8% (hazard ratio [HR], 1.04; 95% CI, 0.99-1.09) and the 15-year disease-specific survival rate was 85.4% vs. 85.4% (HR, 1.01; 95% CI, 0.90-1.14) in high- and low-use areas. Similar patterns were observed for moderately and poorly differentiated cancers. The authors concluded that primary ADT should only be used to palliate disease symptoms or prevent imminent symptoms associated with disease progression.

Tamoxifen applied to breast skin may be a novel therapeutic approach to ductal carcinoma in situ (DCIS)

A randomized, double-blind, placebo-controlled phase II trial published in Clinical Cancer Research compared topical and oral approaches to tamoxifen delivery in women with DCIS[5]. 27 pre- and postmenopausal women were randomized to 4 mg/day of transdermal 4-hydroxytamoxifen gel (4-OHT) vs. 20 mg/day of oral tamoxifen (oral-T) for 6 to 10 weeks before surgical resection. The concentrations of tamoxifen and major metabolites measured by liquid chromatography/tandem mass spectrometry were 0.2 vs. 1.1 ng/mL (P=0.0003) in plasma, and 5.8 vs. 5.4 ng/g (P=0.88) in breast adipose tissue. The primary endpoint was Ki67, a marker for cellular proliferation, labeling in DCIS lesions as measured by immunohistochemistry. Post-therapy, Ki67 decreased by 3.4% in the 4-OHT and 5.1% in the oral-T group (P less than or equal to 0.03 in both, between-group P=0.99). The incidence of hot flashes was similar in both groups; however, significant increases in plasma sex hormone-binding globulin, factor VIII, and von Willebrand factor and a significant decrease in plasma insulin-like growth factor-1 were observed only with oral-T. The similar antiproliferative effect and reduced disruption in endocrine and coagulation parameters observed with 4-OHT compared to oral-T is a promising step in DCIS therapy and breast cancer prevention.

Plants grow toward the sun: Should we take a leaf out of their book?

Amidst evidence pointing to the dangers of sun exposure, particularly the increased risk for malignant melanoma[6], an article in the Journal of Internal Medicine assessed sun avoidance as a risk factor for all-cause mortality[7]. This prospective, 20-year follow-up study included 29,518 Swedish women in the Melanoma in Southern Sweden cohort. Subjects, recruited from 1990 to 1992, were between the ages of 25 and 64 years at the start of the study. Information on sun exposure habits and potential confounders was obtained at baseline, and multivariable flexible parametric survival analysis was applied to the data. There were 2,545 deaths, and an inverse relationship was observed between all-cause mortality and sun exposure habits. Avoiders of sun exposure had an approximately 2-fold higher mortality rate compared with the highest sun exposure group, resulting in excess mortality with a population attributable risk of 3%. Prior research has demonstrated an association between vitamin D deficiency and all-cause mortality[8]; however, no data on vitamin D supplementation or vitamin D levels were obtained in this study. The authors suggested that advising women to practice strict sun avoidance in countries with low solar intensity might harm their health.

ALSO IN THE JOURNALS THIS WEEK:

- The perspective “Chikungunya at the Door” published in the New England Journal of Medicine[9] proved timely given that the first locally acquired case of this mosquito-borne viral fever in Florida also made headlines [10].

- As the marijuana legalization debate rages on, the Proceedings of the National Academy of Sciences added a log to the fire with an article showing that decreased dopamine brain reactivity in abusers is associated with negative emotionality and addiction severity[11].

- According to a 24-year cohort study of United States health professionals in the Annals of Internal Medicine, social integration resulted in a more than 2-fold reduced risk for suicide in men[12].

- Science Translational Medicine published a gene therapy success story: a biological pacemaker for pigs with complete heart block created by minimally invasive somatic reprograming[13].

Dr. Caroline A. Nelson is a 1st year resident, Internal Medicine, NYU Langone Medical Center

Peer reviewed by Mark Adelman, MD, Associate Editor, Clinical Correlations

References:

1. Beck M. Missouri to Allow Med-School Grads to Work as Assistant Physicians. Wall Street Journal. July 16, 2014. http://online.wsj.com/articles/missouri-to-allow-med-school-grads-to-work-as-assistant-physicians-1405547613

2.Lai E, De Lepeleire I, Crumley TM, et al. Suppression of Niacin-induced Vasodilation with an Antagonist to Prostaglandin D2 Receptor Subtype 1. Clin Pharmacol Ther. 2007;81:849–857. http://www.nature.com/clpt/journal/v81/n6/full/6100180a.html

3. HPS2-THRIVE Collaborative Group. Effects of Extended-Release Niacin with Laropiprant in High-Risk Patients. N Engl J Med. 2014;371:203-212. http://www.nejm.org/doi/full/10.1056/NEJMoa1300955

4. Lu-Yao GL, Albertsen PC, Moore DF, et al. Fifteen-Year Survival Outcomes Following Primary Androgen-Deprivation Therapy for Localized Prostate Cancer. JAMA Intern Med. Published online July 14, 2014. http://archinte.jamanetwork.com/article.aspx?articleid=1887061

5. Lee O, Page K, Ivancic D, et al. A Randomized Phase II Presurgical Trial of Transdermal 4-Hydroxytamoxifen Gel versus Oral Tamoxifen in Women with Ductal Carcinoma In Situ of the Breast. Clin Cancer Res. 2014:20;3672. http://clincancerres.aacrjournals.org/content/20/14/3672

6. Chang Y, Barrett JH, Bishop DT, et al. Sun exposure and melanoma risk at different latitudes: a pooled analysis of 5700 cases and 7216 controls. Int J Epidemiol. 2009;38:814–830. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2689397/

7. Lindqvist PG, Epstein E, Landin-Olsson M, et al. Avoidance of sun exposure is a risk factor for all-cause mortality: results from the Melanoma in Southern Sweden cohort. J Intern Med. 2014;276:77-86. http://onlinelibrary.wiley.com/doi/10.1111/joim.12251/abstract

8. Zittermann A, Iodice S, Pilz S, et al. Vitamin D deficiency and mortality risk in the general population: a meta-analysis of prospective cohort studies. Am J Clin Nutr. 2012;95:91-100. http://ajcn.nutrition.org/content/early/2011/12/13/ajcn.111.014779

9. Morens DM, Fauci AS. Chikungunya at the Door — Déjà Vu All Over Again? N Engl J Med. Published online July 16, 2014. http://www.nejm.org/doi/full/10.1056/NEJMp1408509

10. Sun LH. Florida reports first locally acquired case of mosquito-borne virus. Washington Post. July 17, 2014. http://www.washingtonpost.com/national/health-science/florida-reports-first-chikungunya-cases-acquired-in-us/2014/07/17/33a6d6ee-0df4-11e4-b8e5-d0de80767fc2_story.html

11. Volkowa ND, Wanga G-J, Telanga F, et al. Decreased dopamine brain reactivity in marijuana abusers is associated with negative emotionality and addiction severity. PNAS. Published online July 14, 2014. http://www.pnas.org/content/early/2014/07/10/1411228111.abstract

12. Tsai AC, Lucas M. Sania A, et al. Social Integration and Suicide Mortality Among Men: 24-Year Cohort Study of U.S. Health Professionals. Ann Intern Med. 2014;161:85-95. http://annals.org/article.aspx?articleid=1887025

13. Hu Y-F, Dawkins JF, Cho HC, et al. Biological pacemaker created by minimally invasive somatic reprogramming in pigs with complete heart block. Sci Transl Med. 2014(6);245:245ra94. http://stm.sciencemag.org/content/6/245/245ra94

Leave a Reply

Your email address will not be published. Required fields are marked *

*