Primecuts – This Week In The Journals

July 23, 2012

Jennifer Lee Dong, MD

Faculty Peer Reviewed

As we approach the Opening Ceremonies in London this weekend, there has been a great focus on wellness in recent health news. The New York Times reported that the FDA approved a new weight loss drug Qsymia, a combined pill of an appetite suppressant and topiramate [1]. Read on for more breaking news about weight loss and physical activity.

First, though, a theme in medical journals this week surrounds the previously controversial recommendations for prostate cancer screening. In this week’s issue of New England Journal of Medicine, Wilt et al. conducted a clinical trial in which 731 men with localized prostate cancer, mean age 67 years, were randomized to either radical prostatectomy or observation and followed for 10 years [2]. The patients had a median prostate-specific antigen (PSA) level of 7.8 ng/mL (mean 10.1). The primary outcome was all-cause mortality with a secondary outcome of prostate cancer-specific mortality. Patients in the observation group were offered palliative treatment or chemotherapy for symptoms; ultimately, 36 men in this group underwent radical prostatectomy.

Of the 364 patients in each group, 171 (47%) in the prostatectomy group and 183 (49.9%) in the observation group died (hazard ratio=0.8, 95% CI 0.71-1.08, p=0.22) with an absolute risk reduction of 2.9%. Patients who received radical prostatectomy survived for a median of 13 years compared to 12.4 years for those simply observed. For patients with PSA levels less than 10 ng/mL, there was no significant difference in outcomes. However, for patients with PSA levels greater than 10 ng/mL, surgical prostatectomy reduced all-cause mortality by 13.2% (HR=0.67, 95% CI 0.48-0.94). The authors concluded that radical prostatectomy did not cause a significant reduction in all-cause or prostate cancer-specific mortality compared to observation alone. However, patients with high-risk tumors who receive prostatectomy may have slightly improved outcomes [2].

Along similar lines, the Annals of Internal Medicine published the new U.S. Preventive Services Task Force (USPSTF) recommendations for prostate cancer screening [3]. These recommendations replace the 2008 USPSTF guidelines for prostate cancer screening with a grade D recommendation against routine PSA-based screening for prostate cancer. The authors explain that PSA testing may lead to overdiagnosis, detecting many cases of asymptomatic prostate cancer, and/or pseudo-disease, meaning men with asymptomatic cancer as detected by PSA screening have tumor that either does not progress or progresses so slowly so as to not significantly impact mortality. PSA testing often yields false positives which can lead to undue worrying about prostate cancer. In addition, positive PSAs often result in a prostate biopsy, about a third of which are associated with adverse effects such as pain, fever, bleeding, infection, or transient urinary difficulties. Ninety percent of men with PSA-detected prostate cancer in the U.S. receive early treatment with surgery, radiation, or androgen deprivation therapy, all of which can lead to long-term adverse effects including urinary incontinence, erectile dysfunction, bowel dysfunction, gynecomastia, and/or hot flashes. Thus, there is a convincing level of evidence that PSA-based screening for prostate cancer may cause overtreatment associated with a moderate magnitude of associated harm.

According to this review, the U.S. PLCO (Prostate, Lung, Colorectal, and Ovarian) Cancer Screening Trial has shown no decrease in prostate cancer mortality from PSA screening, and the European Randomized Study of Screening for Prostate Cancer (ERSPC) showed a reduction in prostate cancer deaths per 1000 men screened in the 55-69 year-old subgroup. Based on reviewing the available evidence, the USPSTF states with moderate certainty that the benefits of PSA screening do not outweigh the associated risks/harms. Although the USPSTF had previously recommended against PSA-based screening for prostate cancer in men older than 75 years and felt there was insufficient evidence to make a recommendation for younger men, they now recommend against PSA-based screening for prostate cancer in all age groups. For more details regarding emerging commentary and where other medical organizations stand on this guideline, please refer to the clinical guideline document [3].

Mackenzie et al. reported in BMJ the results from a cohort study evaluating the risk of incident breast cancer in older women exposed to spironolactone [4]. Spironolactone possesses anti-androgenic and progestogenic properties, so there is concern that this drug may promote breast cancer development. The authors conducted a retrospective, matched cohort study using a primary care database from the United Kingdom. Over 1 million women aged 55 years or older without a personal history of breast cancer were analyzed. A patient was considered exposed to spironolactone if she received two prescriptions after the age of 55 years; two unexposed women were randomly selected to serve as controls for each exposure patient. The authors looked for a primary outcome of new breast cancer cases identified using Read codes. In the 28,032 women exposed to spironolactone and the 55,961 not exposed, there were a total of 29,491 new cases of breast cancer. The unadjusted rate of breast cancer in each group was 0.39% per year for women exposed to spironolactone versus 0.38% per year for those not exposed. As expected, there was a greater prevalence of women with comorbid diabetes and heart failure in the exposure cohort. Identified risk factors for breast cancer included family history of breast cancer (HR 3.87, 95% CI 2.91-5.14), history of other cancers (HR 1.64, 1.44-1.87), exposure to multiple drug classes (HR 1.04, 1.02-1.06), and exposure to steroids (HR 0.78, 0.65-0.92), most of which carried more weight than the hazard ratio of 0.99 (CI 0.87-1.12) calculated for exposure to spironolactone. Hence, there was no significant evidence to support the concern that spironolactone may increase the incidence of breast cancer in female patients. There also was no relationship between spironolactone dose and risk of developing breast cancer [4].

In wellness news, the Lancet published an early article online by Lee et al. describing the risks of physical inactivity on non-communicable morbid diseases such as coronary artery disease, diabetes, breast cancer, and colon cancer [5]. Prior studies have suggested that physical inactivity, similar to smoking and obesity, may qualify as a risk factor for these diseases and shorten life expectancy. Physical inactivity was defined as an activity level insufficient to meet present recommendations of 15-30 minutes of brisk walking each day. Lee et al. set out to quantify the effect of physical inactivity on the aforementioned major non-communicable diseases. They calculated Population Attributable Fractions (PAFs), an epidemiological measure used to estimate the effect of a risk factor on disease incidence in a population. Utilizing the latest World Health Organization data from 2008, with conservative calculations, the authors estimated that being inactive accounts for 6% of the burden for CAD, 7% for type 2 diabetes, 10% for breast cancer, 10% for colon cancer, and 9% overall for premature mortality. In population numbers, this means that physical inactivity accounted for 5.3 million of 57 million deaths worldwide in 2008. The authors go on to estimate that decreasing physical inactivity by 10% could avert more than 533,000 deaths a year; reducing physical inactivity even more by 25% could avert up to 1.3 million deaths each year. According to this paper, the life expectancy of the world population could be increased by 0.68 years if physical inactivity were eliminated. The greatest increase in energy expenditure was associated with a reduction in CAD; the authors estimate that 6% of the burden of this disease worldwide could be eliminated if all inactive persons became active. However, removal of inactivity had the largest effect on colon cancer, and the least on CAD [5]. One key takeaway message from this study is that recommending physical activity to our patients may delay the development of CAD, diabetes, breast cancer, and colon cancer, and reduce overall mortality.

In the Annals of Internal Medicine, Angell et al. report on the results of a 2006 New York City regulation restricting trans fats in restaurants [6]. They assessed the effect of this regulation on the intake of trans fats and saturated fats pre- and post-implementation. A research group funded by the City of New York and the Robert Wood Johnson Foundation Healthy Eating Research Program conducted brief restaurant lunchtime surveys at 168 NYC locations of 11 fast-food chains (McDonald’s, Burger King, Wendy’s, Subway, Au Bon Pain, Kentucky Fried Chicken, Popeye’s, Domino’s, Pizza Hut, Papa John’s, and Taco Bell). Based on survey responses, the authors tallied up 6969 individual purchases in 2007 and 7885 purchases in 2009. They found a mean trans fat per purchase reduction of 2.4 gms (95% CI –2.8 to –2.0, p <0.001), saturated fat per purchase increase of 0.6 gms (CI 0.1-1.0, p=0.011), mean trans plus saturated fat reduction of 1.9 gms (CI -2.5 to –1.9, p<0.001), and mean trans fat per 1000 kcal decrease of 2.7 gms (CI –3.1 to –2.3, p<0.001). The authors note that purchases with “zero” trans fat increased from 32% to 59%, a result unrelated to the poverty rate of the neighborhood. Products with up to 0.5gm of trans fat can be labeled as containing “zero” trans fat, so it is difficult to determine how many of these products truly contain no trans fat. The greatest absolute decrease of trans fat per purchase occurred in the hamburger chains, averaging 3.8gm less trans fat. Sandwich chains (i.e. Subway, Au Bon Pain) were found to have an increase in trans fat content per purchase by 0.1 gm (p<0.001). Despite an observed slight increase in saturated fat content, the total trans fat and trans plus saturated fat content decreased overall suggesting a net health benefit from the NYC regulation. The question now remains as to whether local food policy such as this one can have a broad positive effect if implemented nationally in the country’s food companies [7].

Other articles of note:

Mueller SK, Sponsler KC, Kripalani S, Schnipper JL. Hospital-Based Medication Reconciliation Practices: A Systematic review. Arch Intern Med. 2012;172(14):1-13.

A systematic review of 26 controlled studies looked at different inpatient medication reconciliation practices and how they might affect clinical outcomes. Evidence currently supports medication reconciliation systems that rely heavily on pharmacists and focus on patients who are at high risk for developing adverse events.

Esbjörnsson J, et al. Inhibition of HIV-1 Disease Progression by Contemporaneous HIV-2 Infection. N Engl J Med. 2012 July 19;367(3):224-232.

Patients who have dual infection with HIV-2 before HIV-1 infection have a delayed onset to developing AIDS as well as the highest levels of CD4+ T-cell counts. The authors believe that concomitant HIV-2 infection may inhibit HIV-1 disease progression.

Ahmed S, Li Q, Liu L, Tsui AO. Maternal deaths averted by contraceptive use: an analysis of 172 countries. The Lancet. 2012 July 14; 380(9837):111-125.

Database review estimated that although over 300,000 women died of maternal causes in 2008, contraceptive use averted approximately 270,000 maternal deaths. Because the numbers of unwanted pregnancies are still high in many developing countries, evidence now supports contraceptive use as an effective approach to preventing and reducing maternal mortality.

Fried MW, Navarro VJ, Afdhal N, et al. Effect of Silymarin (Milk Thistle) on Liver Disease in Patients with Chronic Hepatitis C Unsuccessfully Treated with Interferon Therapy: A Randomized Controlled Trial. JAMA. 2012; 308(3):274-282.

A multi-centered, double-blind, placebo-controlled trial in which participants with chronic hepatitis C viral infection who were previously unsuccessfully treated with interferon-based therapy were randomly assigned to receive low-dose silymarin, high-dose silymarin or placebo and followed over 24 weeks of treatment. Higher doses of silymarin were noted to not significantly reduce ALT levels more than placebo.

Shirani A, Zhao Y, Karim ME, et al. Association Between Use of Interferon Beta and Progression of Disability in Patients With Relapsing-Remitting Multiple Sclerosis. JAMA. 2012;308(3):247-256.

A retrospective cohort study in Canada which found that patients with relapsing-remitting MS did not see a statistically significant reduction in progression of disability from receiving interferon beta when compared to a contemporary control cohort.

Dr. Jennifer Lee Dong is a 3rd year resident at NYU Langone Medical Center

Peer reviewed by Lakshmi Tummala, Associate Editor, Clinical Correlations

Image courtesy of Wikimedia Commons


1. Pollack A. F.D.A. Approvs Qsymia, a Weight-Loss Drug. NY Times 17 July 2012.

2. Wilt TJ, Brawer MK, Jones KM, Barry MJ, Aronson WJ, et al. Radical Prostatectomy versus Observation for Localized Prostate Cancer. N Engl J Med. 2012 July 19;367(3):203-213.

3. Moyer VA. Screening for Prostate Cancer: U.S. U.S. Preventive Services Task Force Recommendation Statement. Ann Intern Med. 2012 July 17; 157(2): 120-134.

4. Mackenzie IS, MacDonald TM, Morant S, Wei L. Spironolactone and risk of incident breast cancer in women older than 55 years: restrospective, matched cohort study. BMJ 2012;345:e4447.

5. Lee IM, Shiroma EJ, Lobelo P, Puska P, Blair SN, Katzmarzyk PT. Effect of physical inactivity on major non-communicable diseases worldwide: an analysis of burden of disease and life expectancy. The Lancet, Early Online Publication, 18 July 2012. doi:10.1016/S0140-6736(12)61031-9.

6. Angell SY, Cobb LK, Curtis CJ, Konty KJ, Silver LD. Change in Trans Fatty Acid Content of Fast-Food Purchases Associated with New York City’s Restaurant Regulation: A Pre-Post Study. Ann Intern Med. 2012 July 17; 157(2):81