Year in Review

DynaMed Weekly Update - Volume 7, Issue 52

Read the complete Weekly Update/earn CME credit

The DynaMed mission is to provide the most useful information to clinicians at the point-of-care. Using DynaMed’s Systematic Literature Surveillance process and 7-Step Evidence-Based Methodology, the editors monitor hundreds of journals and evidence sources to select the most valid and relevant evidence for guiding clinical decisions. Evidence summaries are integrated into more than 3,200 topics written for rapid interpretation by clinicians. Updating occurs daily.

In 2012, the DynaMed Editors considered 30,807 articles and 13,753 articles were included in DynaMed. Each week, from an average of 265 articles added to DynaMed, editors selected articles that were considered “most likely to change clinical practice” and shared 53 articles with DynaMed Weekly Update readers in 2012. In this “Year in Review” issue, the DynaMed Editors share a recap of the 5 most important articles from 2012. We welcome your comments on how your clinical practice was affected by the information presented. Send comments to

We would like to thank our readers for their support and input throughout the year. Your feedback helps improve the DynaMed Weekly Update for the global DynaMed Community.

With our very best wishes for a joyous and peaceful New Year,

The DynaMed Editors

Radical Prostatectomy May Not Reduce Mortality in Most Men with Localized Prostate Cancer Compared to Watchful Waiting

Prostate cancer is the most common cancer in men (not counting skin cancer) and the second most common cause of cancer deaths in men, but many aspects of the management of this disease are controversial. PSA screening has become common over the last 2 decades, and has contributed to increased detection rates of early stage low-risk disease (of note, the United States Preventive Services Task Force [USPSTF] recently issued a statement recommending against routine prostate-specific antigen [PSA] screening for all men, regardless of age [Ann Intern Med 2012 May 21 early online] [DynaMed Weekly Update Vol 7, issue 22]) The best treatment for men with low-risk prostate cancer remains unclear. At the extremes are radical prostatectomy and watchful waiting, but comparative efficacy studies have been inconclusive to date (Cochrane Database Syst Rev 2010 Nov 10;(11):CD006590).

The PIVOT trial compared radical prostatectomy to watchful waiting in 731 men with localized prostate cancer detected by PSA testing. Men ≤ 75 years old (mean age 67 years) were randomized to radical prostatectomy vs. watchful waiting from 1994 to 2002 and were followed for up to 15 years (median follow-up 10 years). At baseline, all men had PSA < 50 ng/mL and life expectancy of ≥ 10 years.

During the trial, 77.2% of the radical prostatectomy group and 79.6% of the watchful waiting group received their allocated treatment. There was no significant difference in all-cause mortality between the 2 groups (47% vs.49.9%) (level 2 [mid-level] evidence) in the overall intention-to-treat analysis, but prostatectomy was associated with a trend toward reduced prostate cancer-related mortality (5.8% vs. 8.4%, p = 0.09). In a subgroup analysis of 251 men with PSA > 10 ng/mL at baseline, however, prostatectomy was associated with significant reductions in both all-cause mortality (48.4% vs. 61.6%, p < 0.05, NNT 8) and prostate cancer-related mortality (5.6% vs. 12.8%, p < 0.05, NNT 14) (N Engl J Med 2012 Jul 19;367(3):203).

For more information, see the Prostate cancer topic in DynaMed.


Preexposure Prophylaxis with Tenofovir Reduces Risk of HIV Transmission in Serodiscordant Heterosexual Couples

As reported in a previous DynaMed Weekly Update (Volume 5, issue 48), preexposure prophylaxis with combination emtricitabine/tenofovir (Truvada) has been shown to reduce the risk of HIV transmission in men who have sex with men (N Engl J Med 2010 Dec 30;363(27):2587). The PrEP trial recently evaluated the prophylactic efficacy of this combination drug and of tenofovir alone in Uganda and Kenya among heterosexual couples in which 1 partner had HIV-1 infection.

A total of 4,758 couples serodiscordant for HIV-1 infection were randomized to 1 of 3 daily oral regimens for the partner without HIV-1 infection: tenofovir 300 mg/day, combination of tenofovir 300 mg plus emtricitabine 200 mg, or placebo. The partner without infection (male partner in 62% of couples) had monthly HIV-1 testing for up to 36 months. All patients received risk reduction counseling, condoms, and HIV-1 prevention information. Various outreach interventions were used to maintain adherence based on local plans and resources. After randomization, 11 couples were excluded for ineligibility.

HIV-1 seroconversion occurred in 22 partners with tenofovir alone, 16 partners with emtricitabine/tenofovir, and 58 partners with placebo. The seroconversion rates per 100 person-years were 0.84 for tenofovir alone (p < 0.001 vs. placebo, NNT 73 for 1 year), 0.61 for emtricitabine/tenofovir (p < 0.001 vs. placebo, NNT 63 for 1 year) and 2.22 for placebo (level 1 [likely reliable] evidence). The seroconversion rates between the 2 active treatments were not significantly different, and both tenofovir-based regimens were associated with significant reductions in seroconversion compared to placebo in subgroup analyses of male and female partners. If the seronegative partner was female, the risk reduction was 71% with tenofovir and 66% with combination therapy. For male seronegative participants the risk reduction was 63% with tenofovir and 84% with combination therapy. There were no significant differences in adverse events across groups (N Engl J Med 2012 Aug 2;367(5):399).

Truvada has recently been approved by the FDA for preexposure prophylaxis in persons at high risk of HIV infection and who engage in sexual activity with partners with HIV infection (FDA Press Release 2012 Jul 16).

For more information, see the HIV infection topic in DynaMed.


Ciprofloxacin for 7 days May Be as Effective as 14 days For Clinical Cure of Acute Pyelonephritis in Women

Oral ciprofloxacin for 7-10 days is a first-line treatment for uncomplicated acute pyelonephritis in nonpregnant women recommended by the Infectious Diseases Society of America and European Society for Microbiology and Infectious Diseases. This recommendation is based in part on a randomized trial that compared ciprofloxacin for 7 days vs. co-trimoxazole for 14 days (JAMA 2000 Mar 22-29;283(12):1583). That trial enrolled young women (median age 25 years) with mild to moderate illness, and the study population was found to have a high prevalence of co-trimoxazole resistance. Treatment duration > 7 days remains common, but longer treatment is associated with increased risk of developing resistance. A new randomized noninferiority trial evaluated the generalizability of 7-day treatment with ciprofloxacin in an older and sicker population.

A total of 248 women (median age 43 years) with a preliminary diagnosis of acute pyelonephritis were randomized to receive ciprofloxacin 500 mg orally twice daily for 7 days vs. 14 days. The first week of treatment was open-label, and the second week was placebo-controlled. 69 women were excluded from the study for incorrect diagnosis, drug resistance, or other ineligibility, and an additional 23 women were excluded from analysis for loss to follow-up or other protocol violations. Bacteremia was present in 27%.

The primary outcome was clinical cure, defined as complete resolution of symptoms during treatment with no recurrence of symptoms or signs of urinary tract infection during follow-up. The clinical cure rates at 10-14 days were 97% with 7-day treatment and 96% with 14-day treatment (noninferiority established) (level 2 [mid-level] evidence). At 42-63 days, both groups had a clinical cure rate of 93% (noninferiority established). There was no significant difference in overall rates of adverse events, but 7-day treatment was associated with lower incidence of mucosal candida infection after the first week (0% vs. 5%, p = 0.036) (Lancet 2012 Aug 4;380(9840):484).

For more information, Acute pyelonephritis see the topic in DynaMed.


Continuing Tamoxifen Beyond 5 Years May Reduce Recurrence and Mortality in Women with Estrogen Receptor-Positive Early Breast Cancer

In women with estrogen receptor (ER)-positive early breast cancer, adjuvant tamoxifen treatment for 5 years has been associated with reduced recurrence and breast cancer mortality for up to 15 years compared to either no tamoxifen treatment or treatment for 1-2 years (Lancet 2011 Aug 27;378(9793):771). Tamoxifen for 5 years is recommended for premenopausal women with early breast cancer (New Zealand Guidelines Group 2009 Aug). The newly-published Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) trial evaluated whether continuing tamoxifen for an additional 5 years would further improve outcomes in a group of 12,894 women. Previous smaller trials have not shown a benefit of such extended tamoxifen treatment.

In the ATLAS trial, women with early breast cancer who had completed 5 years of tamoxifen treatment were randomized without blinding to continued tamoxifen (20 mg/day) for a total 10 years vs. immediate stopping of tamoxifen treatment. ER status was positive in 53% (6,846 women), negative in 10% and unknown in 37%. Women were excluded at clinician discretion for any contraindication to continued tamoxifen. In the 10-year treatment group, treatment could be stopped for emergent definite contraindications and it could be restarted in the 5-year treatment group for definite indication. At publication, 91% had completed 10 years follow-up and 77% had completed 15 years follow-up. The adherence rates in the 10-year treatment group were 84% at 7 years and < 60% at 10 years.

In the prespecified subgroup of ER-positive women, the rates of breast cancer recurrence were 18% with 10-year tamoxifen treatment vs. 20.8% with 5-year treatment (p = 0.002, NNT 36) (level 2 [mid-level] evidence). Tamoxifen for 10 years was associated with reductions in both breast cancer mortality (9.66% vs. 11.6%, p = 0.01, NNT 52) and all-cause mortality (18.6% vs. 21.1% (p = 0.01, NNT 40). The benefits of continued treatment for both recurrence and mortality were significant at ≥ 10 years follow-up, but not at 5-9 years follow-up. There were no significant differences in mortality in analysis of women with ER-negative status or unknown ER status.

The risks of other adverse outcomes occurring prior to recurrence were analyzed in all women regardless of ER status. Continued tamoxifen treatment was associated with increased risk of endometrial cancer (event rate ratio 1.74, 95% CI 1.3-2.34) and pulmonary embolism (event rate ratio 1.87, 95% CI 1.13-3.07), and decreased risk of ischemic heart disease (event rate ratio 0.76, 95% CI 0.6-0.95). There was no significant difference in the rates of endometrial cancer-related death (Lancet 2012 Dec 4 early online).

For more information, see the Endocrine therapy for breast cancer topic in DynaMed.


Probiotics Reduce Risk of Clostridium difficile-Associated Diarrhea in Patients Taking Antibiotics

Diarrhea is a common side effect of antibiotic treatment, which disturbs the balance of bacteria in the gut and may impair the colonization resistance of gastrointestinal flora. Probiotics have previously been shown to reduce rates of antibiotic-associated diarrhea in a large number of trials and systematic reviews (e.g. Aliment Pharmacol Ther 2012 Jun;35(12):1355, Cochrane Database Syst Rev 2011 Nov 9;(11):CD004827). Of particular concern is the specific risk of Clostridium difficile infection, which may cause not just diarrhea, but also colitis and death. A new systematic review of 20 randomized trials evaluated the effects of probiotic prophylaxis specifically on the prevention of C. difficile-associated diarrhea.

A total 3,818 children and adults who were taking antibiotics were randomized to probiotic prophylaxis vs. placebo or no treatment. Probiotic species includedLactobacillus (L. acidophilus, L. casei, L. plantarum, L. rhamnosus GG), Saccharomyces (S. boulardii, S. thermophiles), and Bifidobacterium, with combinations of species in 7 trials. Probiotic treatment lasted for the duration of antibiotic treatment in 7 trials and for up to 14 days after end of antibiotics in the remaining trials. The probiotic dose was > 10 billion colony-forming units/day in 18 trials. Follow-up ranged from the last day of treatment to 3 months.

In the overall analysis, probiotic treatment significantly reduced the incidence of C. difficile-associated diarrhea compared to control (relative risk 0.34, 95% CI 0.24-0.49), The median rate of C. difficile-associated diarrhea in controls was 5%, giving an NNT of 27-40 for probiotic treatment (level 1 [likely reliable] evidence). Probiotics were also associated with reduced incidence of C. difficile-associated diarrhea in children in an analysis of 3 trials with 605 patients (relative risk 0.4, 95% CI 0.17-0.96, NNT 20-417 with diarrhea in 6% of controls). In analyses of specific probiotic species, the incidence of C. difficile-associated diarrhea was significantly reduced with S. boulardii in analysis of 6 trials with 1,232 patients and with a combination of L. acidophilus and L. casei in analysis of 3 trials with 781 patients. There were no significant differences in adverse events (Ann Intern Med 2012 Dec 18;157(12):878).

For more information, see the Probiotics to prevent antibiotic-associated diarrhea,Clostridium difficile infection, and Clostridium difficile infection in children topics in DynaMed.