• CDC Advisers Recommend Against Use of Nasal Spray Flu Vaccine in 2016-2017
• Compression Stocking Therapy for Preventing Post-Thrombotic Syndrome: How Long?
• Meta-Analysis: Phytoestrogens May Help Relieve Some Menopausal Symptoms
• Nanoparticles Prevent Diet-Induced Obesity in Mice
• Dietary Trends Among U.S. Adults: More Whole Grains, Nuts, and Fruit, and
Fewer Sugar-Sweetened Beverages
• Results of So-Called "Liquid Biopsy" Consistent with Regular Tumor Biopsy
• No Mass Fatal Shootings in Australia Two Decades after Semiautomatic Gun Ban
• New Guideline for Prevention and Management of Acute Diarrhea
• Low-Dose Aspirin and Novel Oral Anticoagulants Are Associated with
Complications after Polyp Resection
• Another Possible Benefit of Daily Low-Dose Aspirin
• Are We Underestimating Aspirin's Benefits for Short-Term Recurrent Stroke Prevention?
• Extending Aromatase Inhibitor Therapy for Early Breast Cancer
CDC Advisers Recommend Against Use of Nasal Spray Flu Vaccine
in 2016-2017
By Amy Orciari Herman, Edited by André Sofair, MD, MPH, and William E. Chavey, MD, MS
The CDC's Advisory Committee on Immunization Practices has voted against use of the live attenuated influenza vaccine (LAIV) during the upcoming flu season, citing low efficacy among children during the past three seasons.
The quadrivalent LAIV, given by nasal spray, was estimated to be just 3% effective against any flu virus among children aged 2 to 17 years during the 2016–2017 flu season, according to preliminary data from the U.S. Influenza Vaccine Effectiveness Network. In contrast, the effectiveness of the inactivated influenza vaccine, given by injection, was estimated at 63% in this age group.
In a news release, the CDC notes the potential implications for clinicians who've already ordered vaccine for the upcoming season. Pediatric providers in particular may be affected, given that the nasal spray was used in about a third of child flu vaccinations in recent years. The agency says it will work with vaccine makers in the coming months to ensure the supply.
Dr. Deborah Lehman of NEJM Journal Watch Pediatrics and Adolescent Medicine commented, "This recommendation from the CDC's advisers, supported by the American Academy of Pediatrics, comes as providers are preparing for influenza season. Influenza remains the most commonly occurring vaccine-preventable disease, and routine immunization — this year with the inactivated, injectable vaccine — will prevent illness, hospitalization, and death."
http://www.cdc.gov/media/releases/2016/s0622-laiv-flu.html
https://www.aap.org/en-us/about-the-aap/aap-press-room/pages/AAP-Supports-ACIP-Recommendation-for-Use-of-Inactivated-Flu-Vaccine.aspx?nfstatus=401&nftoken=00000000-0000-0000-0000-000000000000&nfstatusdescription=ERROR%3a+No+local+token
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BMJ 2016 May 31; 353:i2691
Compression Stocking Therapy for Preventing Post-Thrombotic Syndrome:
How Long?
Two years of therapy was more effective than 1 year.
Post-thrombotic syndrome is a common complication of deep venous thrombosis (DVT) that causes symptoms ranging from pain and swelling to ulceration. Elastic compression stockings often are prescribed to prevent this complication, but the most effective duration of treatment is unclear. Researchers in the Netherlands conducted a noninferiority trial of compression stocking use in 518 patients who had adhered to compression stocking therapy and had not developed post-thrombotic syndrome during 1 year after experiencing proximal lower-extremity DVT. Half of the participants were told to stop wearing compression stockings at 1 year, and the other half were told to continue therapy for another year.
In intent-to-treat analysis, incidence of post-thrombotic syndrome was 13% in the 2-year group and 20% in the 1-year group — a significant 7% absolute difference (number needed to treat, 14); noninferiority of 1 year versus 2 years of therapy could not be established. Quality of life, a secondary outcome, did not differ between groups.
COMMENT: In this trial, compression stocking use for 2 years was more effective than 1 year of use in preventing post-thrombotic syndrome. In contrast, the SOX trial showed no preventive benefit from 2 years of treatment with compression stockings versus sham stockings (NEJM JW Gen Med Jan 15 2014 and Lancet 2014; 383:880); however, adherence to treatment was lower in the SOX study than in this one, and sham stockings might have conferred some benefit.
CITATION(S):Mol GC et al. One versus two years of elastic compression stockings for prevention of post-thrombotic syndrome (OCTAVIA study): Randomised controlled trial. BMJ 2016 May 31; 353:i2691.
(http://dx.doi.org/10.1136/bmj.i2691)
http://www.bmj.com/content/353/bmj.i2691?ijkey=38ae6fb837dde47266ea18d2fab
7430f15168003&keytype2=tf_ipsecsha
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Meta-Analysis: Phytoestrogens May Help Relieve Some Menopausal Symptoms
By Amy Orciari Herman, Edited by Lorenzo Di Francesco, MD, FACP, FHM
Phytoestrogens might offer some relief for hot flashes and vaginal dryness associated with menopause, suggests a JAMA meta-analysis. The researchers, however, advise caution in interpreting the findings.
The analysis included over 60 randomized trials in which plant-based therapies were compared with placebo or no treatment in nearly 6700 perimenopausal, menopausal, or postmenopausal women. Among the findings:
- Use of any phytoestrogen — and soy isoflavones in particular — was associated with significant, albeit modest, reductions in the number of daily hot flashes and in vaginal dryness scores. Phytoestrogens showed no effect on night sweats.
- Some non-Chinese herbal remedies (e.g., pine bark extract) appeared to relieve hot flashes, while Chinese herbals (e.g., dong quai) did not.
- Black cohosh generally had no effect on vasomotor symptoms.
Diane E. Judge, APN/CNP and contributing editor for NEJM Journal Watch Women's Health, says that the study "offers some encouragement to the many women who use plant-based remedies, but I agree with the authors: we still lack rigorous efficacy and safety studies."
http://jama.jamanetwork.com/article.aspx?articleid=2529629
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Proc Natl Acad Sci U S A 2016 May 17; 113:5552
Nanoparticles Prevent Diet-Induced Obesity in Mice
Transforming white fat to brown fat might be the key to a new therapy.
In humans, the much more prevalent white fat cells store fat, but brown fat cells burn fat. When researchers discovered that white fat can be converted into brown fat in vitro after stimulation by either rosiglitazone or a prostaglandin E2 analogue (NEJM JW Gen Med Oct 15 2008 and Nature 2008; 454:961), the idea that these molecules could be used to treat or prevent obesity was born. These agents also stimulate angiogenesis and attract the new blood supply that newly created brown fat cells need. But how could the same transformation be achieved in vivo?
A multi-institutional team created nanoparticles with two properties: (1) they contained either rosiglitazone or the prostaglandin E2 analogue; (2) they adhered selectively to the endothelium of vasculature within white fat. In obese mice, these nanoparticles homed to white fat, stimulated angiogenesis, transformed white fat into brown fat, inhibited weight gain, and improved blood levels of cholesterol, triglycerides, and insulin.
COMMENT: These results in mice someday might lead to using nanoparticles to treat obesity in humans, with two caveats. First, in humans, thiazolidinediones (such as rosiglitazone) taken systemically cause weight gain (which is not attributable entirely to fluid retention), so these results in mice might not be duplicable in humans; presumably, it will depend on whether nanoparticle delivery in humans will target the favorable white-fat effect specifically. Second, stimulation of angiogenesis includes theoretical risks: If the process in not restricted to white fat, it could enhance growth of early tumors elsewhere in the body.
CITATION(S): Xue Y et al. Preventing diet-induced obesity in mice by adipose tissue transformation and angiogenesis using targeted nanoparticles. Proc Natl Acad Sci U S A 2016 May 17; 113:5552.
(http://dx.doi.org/10.1073/pnas.1603840113)
http://www.pnas.org/content/113/20/5552?ijkey=
05d2445d79b3edbb36b6b209bd842a2287c08c67&keytype2=tf_ipsecsha
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Dietary Trends Among U.S. Adults: More Whole Grains, Nuts, and Fruit, and Fewer Sugar-Sweetened Beverages
By Thomas L. Schwenk, MD
The average U.S. diet improved somewhat in recent years, but nearly half of adults still consume poor-quality diets, according to a JAMAstudy.
Researchers assessed trends in dietary patterns by examining nationally representative survey data collected between 1999 and 2012 from roughly 34,000 adults. During the study period, there were significant increases in mean daily consumption of whole grains (by 0.43 servings); nuts, seeds, and legumes (0.26 servings); and whole fruit (0.15 servings). Mean daily consumption of 100% fruit juice and sugar-sweetened beverages decreased significantly (by 0.11 servings and 0.49 servings). The proportion of diets rated as poor declined from 56% to 46%; the proportion of those rated as ideal increased from 0.7% to 1.5%.
Diet scores improved for all subgroups stratified by education and income, but the disparities present in earlier scores widened over time in favor of those with higher education and income levels.
Comment: Improvements in some dietary components are encouraging, but their effects on overall diet quality were modest.
http://jama.jamanetwork.com/article.aspx?articleid=2529628
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Results of So-Called "Liquid Biopsy" Consistent with Regular Tumor Biopsy
By Kelly Young, Edited by Susan Sadoughi, MD, and André Sofair, MD, MPH
In advanced cancer, genetic mutations detected in blood samples appear to be similar to mutations found in tumor biopsies, according to an industry-funded study presented at the American Society of Clinical Oncology’s annual meeting. An accurate liquid biopsy test could help physicians detect cancer, monitor changes, and guide treatment in a less invasive way.
Using the Guardant360 test, which targets 70 genes, researchers collected blood samples and analyzed circulating tumor DNA (ctDNA) from over 15,000 patients with advanced cancer. Results from nearly 400 of these patients were compared with tissue samples from their tumors. The ctDNA had a sensitivity of 78%–86%, depending on the cancer type. When blood and tumor specimens were collected less than 6 months apart, the accuracy was 98%.
The researchers also compared ctDNA with a genomic analysis of tumor tissue from The Cancer Genome Atlas. ctDNA testing revealed possible treatment options — including FDA-approved drugs and clinical trial eligibility — for 64% of patients tested.
http://meetinglibrary.asco.org/content/171265-176
http://www.asco.org/about-asco/press-center/news-releases/liquid-biopsy-may-help-guide-treatment-decisions-advanced?et_cid=37909662&et_rid=754405735&linkid=Read+more
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No Mass Fatal Shootings in Australia Two Decades after Semiautomatic
Gun Ban
By Amy Orciari Herman, Edited by Susan Sadoughi, MD, and Richard Saitz, MD, MPH, FACP, FASAM
Australia has experienced no mass fatal shootings since it banned rapid-fire long guns in 1996, a JAMA study finds. The ban included guns already owned by citizens and mandated government buyback of all prohibited firearms.
Using national government statistics and news reports, researchers compared firearm deaths during two decades before the ban (1979 through 1996) and two decades afterward (1997 to May 2016). Before Australia's ban, there were 13 mass fatal shootings, with 104 deaths — versus none afterward.
Total firearm deaths also declined after the ban, from 3.6 per 100,000 population to 1.2 per 100,000. However, at the same time, non-firearm suicides and homicides also declined, so the reduction in total firearm deaths could not be directly attributed to the gun ban.
A JAMA editorialist urges U.S. citizens to follow Australia's lead in demanding laws to limit gun violence.
Separately, New England Journal of Medicine editorialists call for "universal background checks ... for every gun sale in every setting" in the U.S., as well as a ban on "assault weapons."
http://jama.jamanetwork.com/article.aspx?articleid=2530362
http://jama.jamanetwork.com/article.aspx?articleid=2530361
http://www.nejm.org/doi/full/10.1056/NEJMe1608173?query=
pfw&jwd=000101421649&jspc=
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Am J Gastroenterol 2016 May; 111:602
New Guideline for Prevention and Management of Acute Diarrhea
Recommendations include those on preventing traveler's diarrhea, which patients often ask about.
Sponsoring Organization: American College of Gastroenterology (ACG), Audience: Gastroenterologists, primary care providers
Background and Objective: In this new comprehensive guideline, researchers developed graded recommendations on diagnosis, management, and prevention of acute diarrheal infections based on a systematic review of evidence.
Key Recommendations:
- In acute diarrhea (duration, 1–14 days), perform stool cultures and new culture-independent molecular assays (if available) when a patient is at high risk of spreading disease or during outbreaks.
- Consider stool diagnostic tests in presence of dysentery, moderate-to-severe disease, or symptom duration >7 days.
- Supplement traditional diagnostic stool tests (culture, microscopy with or without special stains, immunofluorescence, antigen testing), which are usually negative in acute diarrhea, with FDA-approved culture-independent molecular methods if available.
- Do not conduct antibiotic sensitivity testing in acute diarrhea.
- The use of a fecal leukocyte test or fecal lactoferrin to guide more appropriate use of cultures is “imprecise and probably unnecessary.”
- With a few exceptions, most patients can adequately rehydrate with water, juice, sports drinks, soups, and salty crackers.
- Do not treat acute diarrhea with probiotics and prebiotics except for postantibiotic diarrhea.
- Treat mild-to-moderate traveler's diarrhea (TD) with bismuth subsalicylate except where contraindicated (e.g., use of other salicylates). Warn patients about the harmless black tongue and black stools that result.
- Loperamide remains an excellent treatment for TD. Titrate the dose to avoid posttreatment constipation, and do not give for >48 hours. Loperamide may even be safe in a dysentery presentation that would increase the risk for an invasive pathogen, provided it is combined with antibiotic therapy.
- Do not conduct empiric antibiotic therapy in acute diarrheal infection, except in cases of TD in which a bacterial cause is deemed highly likely. Most community-acquired acute diarrhea is viral in origin.
- Treat TD with a single-dose or 3-day course of quinolones or single-dose azithromycin (1000 mg), except for suspected or cultured Shigella, which requires a 5-day course.
- Endoscopic evaluation is not recommended for this duration of symptoms.
- Specific handwashing measures and alcohol-based hand sanitizers have limited value for most TD but could be useful in preventing cruise ship outbreaks of norovirus and institutional outbreaks, or in areas of endemic diarrhea.
- For prophylaxis of TD, consider bismuth subsalicylate two tablets (2.1 g) four times daily at meals and bedtime to provide 60% risk reduction for trips up to 2 weeks but usually not for longer trips; lower doses are associated with reduced protection.
- Do not use prebiotics, probiotics, and synbiotics (combinations of prebiotics and probiotics) for TD prophylaxis.
- Antibiotic prophylaxis for TD is recommended, but only in high-risk groups and for short-term use. This limited role for chemoprophylaxis is being reevaluated with increasing awareness of the high frequency and impact of postinfectious irritable bowel syndrome and the availability of rifaximin, which has desirable features and safety profile compared with quinolones for prophylaxis.
COMMENT: Although it seems that gastroenterologists evaluate fewer patients with acute diarrhea than with chronic diarrhea, we do sometimes see acute diarrhea, and patients often ask about how to prevent traveler's diarrhea. A useful feature of this guideline is an algorithm that details a management approach to acute diarrhea based on watery versus dysenteric presentation and duration of symptoms and which covers both diagnostic assessment and treatment.
CITATION(S): Riddle MS et al. ACG clinical guideline: Diagnosis, treatment, and prevention of acute diarrheal infections in adults. Am J Gastroenterol 2016 May; 111:602. (http://dx.doi.org/10.1038/ajg.2016.126)
http://www.ncbi.nlm.nih.gov/pubmed/27068718?access_num=
27068718&link_type=MED&dopt=Abstract
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Gastrointest Endosc 2016 May 14
Low-Dose Aspirin and Novel Oral Anticoagulants Are Associated with Complications after Polyp Resection
Among other novel findings, combining low-dose aspirin with these anticoagulants or with other common drugs increased bleeding risk compared with aspirin alone.
In a population-based study, researchers retrospectively evaluated risk factors for complications from colorectal polyp resection in 345,546 patients in Japan.
Endoscopic mucosal resection (EMR) was performed in 64%, polypectomy in 32%, and endoscopic submucosal dissection (ESD) in 5%. The overall rates of bleeding (postprocedure and requiring endoscopic hemostasis or transfusion), surgically treated bowel perforation, cardiovascular events, cerebrovascular events, and deaths per 1000 patients were 32.5, 0.5, 0.05, 0.9, and 1.3, respectively.
In a multivariate analysis, bleeding risk was positively associated with male gender, various comorbidities (heart failure, cerebrovascular disease, dementia, chronic lung disease, rheumatoid disease, peptic ulcer, diabetes, renal disease, and liver disease), ESD, polyp size ≥2 cm, and various medications, including low-dose aspirin, novel oral anticoagulants (NOACs — dabigatran, rivaroxaban, and edoxaban), warfarin, nonsteroidal anti-inflammatory drugs (NSAIDs), thienopyridines, and steroids. Combination therapy of low-dose aspirin and another agent compared with low-dose aspirin therapy alone yielded the highest risk for bleeding (odds ratios, 3.2 for warfarin as co-agent; 3.3 for NOACs; 3.4 for NSAIDs; 1.9 for steroids) among all demographic and clinical factors evaluated.
Perforation risk was positively associated with male gender, renal disease, ESD, lesion size ≥2 cm, high annual procedure volume, and (for reasons not completely clear) use of warfarin, NSAIDs, or steroids.
COMMENT: The strength of this study is its huge size compared with multiple previous trials on this topic. Novel observations include the clear increased risk for bleeding in patients on low-dose aspirin or NOACs, the additive bleeding risk of combining low-dose aspirin with other agents, and the association of perforation risk with warfarin, NSAIDs, and steroids. Chronic corticosteroid use has been previously implicated as a risk factor for mechanical colon rupture from colonoscope passage, but these data suggest that they also increase the risk for polypectomy-associated perforation.
Note to readers: At the time NEJM Journal Watch reviewed this paper, its publisher noted that it was not in final form and that subsequent changes might be made.
CITATION(S): Niikura R et al. Factors predicting adverse events associated with therapeutic colonoscopy for colorectal neoplasia: A retrospective nationwide study in Japan. Gastrointest Endosc 2016 May 14; [e-pub].
(http://dx.doi.org/10.1016/j.gie.2016.05.013)
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Obstet Gynecol 2016 Jun 6
Another Possible Benefit of Daily Low-Dose Aspirin
Retrospective study suggests increased survival after treatment for endometrial cancer.
Low-dose aspirin can lower risk for colorectal cancer and increase survival in patients following treatment for colon cancer. To explore the impact of daily aspirin on survival in women who received standard treatment for endometrial cancer, researchers performed a retrospective analysis including 158 women with endometrial cancer who were taking daily oral low-dose aspirin (81–100 mg) and 1529 women who were not taking aspirin.
At an overall median follow-up of 31.5 months, 5-year disease-free-survival rates were 90% and 81% among women who did take and did not use low-dose aspirin, respectively (P=0.015). This beneficial effect was most prominent in young women, obese women, and those with favorable tumor histology. Women in the aspirin group were more likely to be taking antihypertensive and antihyperglycemic medications (for example, metformin was being taken by 42% of aspirin users and 9% of nonusers [P<0.001]).
COMMENT: This study's weaknesses include its retrospective design, small sample size, and marked heterogeneity between groups. Based on chart review, the investigators were unable to determine the medical indication for or duration of low-dose aspirin use. It's likely that aspirin was being taken to prevent cardiovascular events; compared with nonusers, aspirin users had higher rates of obesity, hypertension, diabetes, and dyslipidemia. Nonetheless, if this inexpensive, safe intervention can be confirmed to improve survival in a large randomized trial involving women with endometrial cancer, the health benefit would be great.
CITATION(S): Matsuo K et al. Association of low-dose aspirin and survival of women with endometrial cancer. Obstet Gynecol 2016 Jun 6; [e-pub]. (http://journals.lww.com/greenjournal/Abstract/publishahead/Association_of_
Low_Dose_Aspirin_and_Survival_of.98720.aspx)
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Lancet 2016 May 18
Are We Underestimating Aspirin's Benefits for Short-Term Recurrent Stroke Prevention?
A meta-analysis suggests so, although the practice context has changed.
Although aspirin is in widespread use for long-term secondary prevention of stroke, its effects on reducing stroke in the first few weeks and months after a transient ischemic attack (TIA) or stroke have been studied less. Because the first 90 days after a TIA are the highest risk period for recurrent vascular events, the effects of aspirin during this period are of particular interest.
These authors performed an analysis of 12 randomized, controlled trials of aspirin after TIA or stroke that included information on timing and severity of vascular events. A total of 15,778 participants were included; 11 trials studied aspirin alone versus a control. In these 11 trials, aspirin significantly reduced the 6-week risk for recurrent ischemic stroke by close to 60% (hazard ratio, 0.41). Aspirin also reduced ischemic strokes in the 6- to 12-week period (HR, 0.60). Aspirin did not significantly affect events beyond 12 weeks. Three trials included patients enrolled within 48 hours of stroke onset. In these trials, stroke within 14 days was reduced with aspirin in patients who had mild deficits at entry but not in patients with severe deficits.
COMMENT: This analysis shows that aspirin may be more beneficial for short-term reduction of stroke compared with long-term use. However, many of the included trials were conducted in the 1980s and 1990s, before widespread use of statins. In addition, blood pressure control was likely to be less stringent in the early trials. As an element in the current era of multimodal stroke prevention, aspirin is likely to be less effective than it was in this evaluation. However, clinicians should still institute aspirin therapy soon after making a diagnosis of TIA or ischemic stroke.
CITATION(S): Rothwell PM et al. Effects of aspirin on risk and severity of early recurrent stroke after transient ischaemic attack and ischaemic stroke: Time-course analysis of randomised trials. Lancet 2016 May 18; [e-pub].
(http://dx.doi.org/10.1016/S0140-6736(16)30468-8);
Hankey GJ.The benefits of aspirin in early secondary stroke prevention. Lancet 2016 May 18; [e-pub].
(http://dx.doi.org/10.1016/S0140-6736(16)30511-6)
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N Engl J Med 2016 Jun 5
Extending Aromatase Inhibitor Therapy for Early Breast Cancer
Treatment with letrozole for an additional 5 years after initial treatment reduced risk for disease recurrence.
In the prior MA.17 trial (N Engl J Med 2003; 349: 1793), investigators demonstrated that after 4 to 6 years of adjuvant tamoxifen therapy, administration of the aromatase inhibitor (AI) letrozole for 5 years versus placebo significantly improved disease-free survival (DFS) for postmenopausal women with early breast cancer.
To determine whether extending the duration of letrozole for an additional 5 years would further reduce the risk for recurrence, these investigators conducted a randomized, double-blind, placebo-controlled, phase III trial (MA.17R) of 1918 postmenopausal patients with hormone-receptor–positive, early-stage disease who had received 4.5 to 6.0 years of adjuvant AI therapy, preceded in most by tamoxifen. Within 2 years of completing AI therapy, disease-free patients were randomized to receive letrozole or placebo for another 5 years.
At a median follow-up of 6.3 years, 165 DFS events had occurred, including 42 distant recurrences in the letrozole group and 53 distant recurrences in the placebo group. Contralateral breast cancer occurred in fewer patients receiving letrozole than placebo (13 vs. 31). Overall survival (OS) was identical between the two groups. Extended letrozole therapy resulted in further reduction in the odds of a breast cancer event. The 5-year DFS was 95% for the letrozole arm and 91% for the placebo arm; only about 1% of the difference was accounted for by distant recurrences.
COMMENT: These results raise the issue of whether extended AI therapy should be recommended for all patients. Although quality-of-life data suggest equivalence between the two treatment arms, self-selection may have occurred, as patients able to complete the first 5 years of letrozole with few adverse effects may have been willing to be rerandomized for further treatment. Additionally, there may be tumors for which this strategy is more relevant, based on grade, size, nodal involvement, etc. As is often the case, these data suggest that recommendations must be individualized.
CITATION(S): Goss PE et al. Extending aromatase-inhibitor adjuvant therapy to 10 years. N Engl J Med 2016 Jun 5; [e-pub].
(http://dx.doi.org/10.1056/NEJMoa1604700)
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