PrimeCuts

Primecuts – This Week In The Journals

September 3, 2013

By Molly Somberg, MD, MPA

Faculty Peer Reviewed

This Labor Day weekend marked the unofficial end of summer, which meant the end of long lazy beach days and back to school for millions of American children. For many adults, and kids alike, this past weekend also marked the kickoff of the college football season. Whether a Buckeye, a Bulldog or a Bobcat (which is NYU’s mascot, although the university no longer has a football team), football season means alumni have the chance to show off their college pride, rooting for their alma mater, no matter how good or bad their beloved team may be. In other sports news this week, the US Open is in full swing in Flushing, Queens. This event brings tennis fans from around the world to The Big Apple to watch tennis superstars go head to head on the hard court. Now from the world of sports to that of medicine, there is equally exciting news to discuss…

As most practitioners are aware, rising healthcare costs are a pressing issue for many medical professionals. Providing efficient healthcare is crucial for controlling healthcare costs in the United States. A recent article out this month investigates a mechanism for reducing one type of medical inefficiency: redundant lab draws. Current guidelines about the frequency of lipid testing are dictated by the Adult Treatment Panel III, which suggests annual lipid panels in patients with coronary artery disease (CAD).[1]   This study, in the August 12/26, 2013 JAMA Internal Medicine, is a retrospective cohort study, in which the researchers identified 35,191 patients with CAD at the 7 VA Medical Centers in the Houston, Texas network. These patients were then stratified by the following categories: LDL level, if any future testing was performed on an annual basis, and if any treatment intensification occurred after testing. Treatment intensification was defined as an increase in a lipid-lowering medication dose or addition of another lipid-lowering medication to the patient’s medication regimen. The authors found that of this large group: 6290 patients had an LDL<100, did not receive any treatment intensification and no repeat lipid panel; 9200 patients also had their LDL<100, did not receive treatment intensification but had a repeat lipid panel performed; 12,457 were at an LDL<100 but received treatment intensification and 7244 were still at an LDL>100. This translates into 32.9% of patients (9200 patients) with LDL levels less than 100 receiving additional lipid testing without any treatment intensification or 12,686 lipid panels that did not need to be performed at $16.08 per test. Thus, the authors found $203,990 in excessive costs at only one institution. One could imagine how rethinking annual lipid panel guidelines might help save enormous medical costs if changes to these guidelines were implemented nationwide. [2]

In other news, a recent article in Circulation reaffirmed the effectiveness of intermittent pneumatic compression (IPC) in preventing venous thromboembolism in the lower extremities of hospitalized patients. The authors conducted a meta-analysis of 70 randomized controlled trials, which compared IPC to: TEDS, pharmacologic thromboprophylaxis, no prophylaxis and combined IPC/pharmacologic thromboprophylaxis. The authors found that IPC was more effective than no prophylaxis or TEDS, equally as effective as pharmacologic prophylaxis, but the combination of IPC and pharmacologic prophylaxis was most effective. This study should trigger clinicians to reconsider DVT prophylaxis for hospitalized patients, especially those who are at high-risk for thromboembolism. Such patients should ideally benefit from pharmacologic prophylaxis as well as ICP, although standard practice typically dictates choosing only one method of prophylaxis even in patients who can tolerate both types.[3]

This week’s JAMA featured a timely article about how Accountable Care Organizations (ACOs) impact the cost and quality of healthcare. This quasi-experimental study compared Medicare patients enrolled in a commercial ACO in Massachusetts to Medicare beneficiaries in all other types of plans in the state. Utilizing difference-in-difference regression models, the authors found that Medicare beneficiaries receiving care via an ACO model saved 3.4% between year 1 and 2 of the study. The authors discovered that most of the savings were secondary to lower outpatient care costs, including less spending on procedures, imaging and lab tests. Of note, the authors also found that ACO-enrolled patients were more likely to have their LDL tested if they were diabetics or had cardiovascular disease, but the study did not otherwise show any significant difference regarding the quality of care. Although there was a limited impact on the quality of care, this study is proof that ACOs are an effective means of bending the healthcare cost curve, one of the central goals of the recently passed Affordable Care Act.[4]

The New England Journal of Medicine featured a non-inferiority trial comparing apixaban (Brand Name: Eliquis), an oral twice-a-day factor Xa inhibitor, to subcutaneous enoxaparin bridged to warfarin, for the treatment of venous thromboembolism. The trial was a randomized double-blinded study funded by Pfizer and Bristol-Myers Squibb, the manufacturer of apixaban. The authors found that there was no significant difference in the percentage of recurrent venous thromboembolism, or death related to venous thromboembolism, between the apixaban group versus the conventional treatment group, but that there was a significant reduction in major bleeding risk with apixaban as compared to warfarin. These findings suggest that apixaban may be a safer method for anticoagulation in patients with venous thromboembolism than warfarin. However, it should be noted that apixaban has not yet been studied in patients with cancer or with impaired renal function, thus this study may only be generalizable to a narrow patient population and is likely to be far more expensive than conventional treatment with warfarin.[5]

Other interesting reads this week…

1. Hong, Jin-Liern, Christoph R. Meier, Robert S. Sandler, Susan S. Jick, and Til Sturmer. “Risk of Colorectal Cancer after Initiation of Orlistat: Matched Cohort Study.” British Medical Journal 347:f5039 (2013): 27 Aug. 2013  http://www.bmj.com/content/347/bmj.f5039

Given recent animal studies, which showed that the top-selling anti-obesity medication orlistat (Brand Name: Alli) increased the risk of aberrant colonic crypt foci in rats, a team of epidemiologists at UNC School of Public Health conducted a retrospective matched cohort study utilizing data from the UK to assess the risk of colorectal cancer in patients using orlistat. The authors found that the incidence rate of colon cancer was not statistically significantly different between orlistat users and non-users. While these findings reassure the reader that orlistat is safe, it should be noted that the median follow up time in this study was just under 3 years, thus this study did not account for the possible long-term effects of orlistat use, which are still unknown.

2. Wharam, J. Frank, Fang Zhang, Bruce E. Landon, Stephen B. Soumerai, and Dennis Ross-Degnan. “Low-Socioeconomic-Status Enrollees In High-Deductible Plans Reduced High-Severity Emergency Care.” Health Affairs 32.8 (2013): 1398-406. Aug. 2013.  http://content.healthaffairs.org/content/32/8/1398.full.pdf+html

With the Affordable Care Act in its implementation phase, one expected change is an increase in the number of people choosing high-deductible plans, or plans with low premiums, but higher out-of-pocket costs when one gets sick. The authors of this study utilized data from Massachusetts, which has had an individual mandate for many years, to study how high-deductible plans impact the behavior of individuals. The authors found that lower socioeconomic status (SES) individuals reduced high-severity ED visits by 25-30% after enrolling in a high-deductible plan, and that hospitalizations in the first year declined by 23%, but then increased in the subsequent year. From this, the authors implied that lower SES individuals did not seek necessary care because of high out-of-pocket costs, which led to subsequent higher costs as patients required more hospitalizations later on for poorly controlled morbidities. Of note, the high-deductible plans had no effect on the behavior of high SES individuals.

3. Erichsen, Rune, John A. Baron, Elena M. Stoffel, Soren Laurberg, Robert S. Sandler, and Henrik Toft Sorensen. “Characteristics and Survival of Interval and Sporadic Colorectal Cancer Patients: A Nationwide Population-Based Cohort Study.” The American Journal of Gastroenterology 108 (2013): 1332-340. Aug. 2013.  http://www.nature.com/ajg/journal/v108/n8/pdf/ajg2013175a.pdf

In this study, Danish researchers utilized multivariate logistical regression models to compare interval colorectal cancers (defined as CRCs diagnosed within 1-5 years of a colonoscopy) to CRCs diagnosed greater than 10 years after colonoscopy to sporadic CRCs (defined as no prior colonoscopies). The authors found that interval CRCs were more common in older, female patients with comorbidities, and that the tumors were more likely to be proximal. However, interval CRCs were found at stages similar to sporadic CRCs. Based on these results, the authors concluded that interval CRCs are more likely due to missed lesions on colonoscopy, not more aggressive tumors.

Molly Somberg, MD, MPA is a first year internal medicine resident at NYU Langone Medical Center

Peer Reviewed by Brian Greet, MD, Associate Editor, Clinical Correlations

Image courtesy of Wikimedia Commons

References

1.  Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA. 2001;285(19):2486-2497.

2.   Virani, Salim S., LeChauncy D. Woodard, Degang Wang, Supicha S. Chitwood, Cassie R. Landrum, Tracy H. Urech, Kenneth Pietz, G. John Chen, Brian Hertz, Jeffrey Murawsky, Christie M. Ballantyne, and Lauren A. Petersen. “Correlates of Repeat Lipid Testing In Patients with Coronary Heart Diseae.” JAMA Internal Medicine 173.15 (2013): 1439-444. 12/26 Aug. 2013.  http://archinte.jamanetwork.com/article.aspx?articleid=1726982

3. Ho, Kwok M., and Jen Aik Tan. “Stratified Meta-Analysis of Intermittent Pneumatic Compression of the Lower Limbs to Prevent Venous Thromboembolism in Hospitalized Patients.” Circulation 128 (2013): 1003-020. 28 Aug. 2013.  http://circ.ahajournals.org/content/128/9/1003.abstract

4.  McWilliams, J. Michael, Bruce E. Landon, and Michael E. Chernew. “Changes in Health Care Spending and Quality for Medicare Beneficiaries Associated With a Commercial ACO Contract.” JAMA: The Journal of the American Medical Association 310.8 (2013): 829-36. 28 Aug. 2013.  http://jama.jamanetwork.com/article.aspx?articleid=1733718

5.  Agnelli, Giancarlo, Harry R. Butler, Alexander Cohen, Madelyn Curto, Alexander S. Gallus, Margot Johnson, Urszula Masiukiewicz, Raphael Pak, John Thompson, Gary E. Raskob, and Jeffrey I. Weitz. “Oral Apixaban for the Treatment of Acute Venous Thromboembolism.” The New England Journal of Medicine 369.9 (2013): 799-808. 29 Aug. 2013.  http://www.nejm.org/doi/full/10.1056/NEJMoa1302507

 

Primecuts – This Week In The Journals

August 26, 2013

By Brian Greet, MD

Faculty Peer Reviewed

On the twenty first of this month, rebels proclaimed that they had been attacked by the Syrian government with the use of chemical warfare. Medicins Sans Frontieres is reporting this week that they treated approximately 3,600 patients with “neurotoxic symptoms” of whom 355 had expired. Bart Janssens, MSF Director of Operations, stated “MSF can neither scientifically confirm the cause of these symptoms or establish who is responsible for the attack.” He went on to say, “However, the reported symptoms of the patients, in addition to the epidemiological pattern of the events—characterized by the massive influx of patients in a short period of time, the origin of the patients, and the contamination of medical and first aid workers—strongly indicate mass exposure to a neurotoxic agent. This would constitute a violation of international humanitarian law, which absolutely prohibits the use of chemical and biological weapons.” Per MSF, symptoms of patients included dilated pupils, convulsions and respiratory difficulty with many being treated with atropine. [1] As Washington continues to weigh its options on how to react to what’s happening in the Damascus region, many within Washington were celebrating the fiftieth anniversary of Dr. Martin Luther King Jr.’s “I Have a Dream” speech this week. Tens of thousands of people marched to the Martin Luther King Jr. Memorial and down the National Mall on Saturday in honor of Dr. King.

Marching right along from headlines to medical news, a new retrospective study in Stroke looking at “ultra-early” thrombolytic administration showed that earlier administration resulted in significantly improved outcomes. Based off a prior single center study that evaluated the outcome of lytic administration within 90 minutes of symptom onset, this new multi-center retrospective study looked to evaluate for the same in a larger cohort. Looking at 6,856 patients with ischemic stroke from ten different European stroke centers, they found that thrombolytic administration within 90 minutes in those patients with an NIH stroke scale of 7-12 had improved three month neurologic outcomes and reduced intracranial bleeding events compared to those receiving therapy after 90 minutes. Improved neurologic outcomes were defined by a Rankin scale of 0-1. Mortality, however, did not differ between groups. Such findings further emphasize the need to take early signs of stroke seriously and that patients should be brought to the closest stroke center as quickly as possible. [2]

In the world of infectious disease, a recent trial published in the Lancet looked to determine whether or not early antiretroviral therapy (ART) helps to improve outcomes in HIV-infected infants. The CHER trial was an open label randomized trial of infants less than 12 weeks that took place in two South African trial sites. 377 infants were randomized to either receive deferred ART, immediate ART for 40 weeks or immediate ART for 96 weeks, with subsequent treatment interruption. When compared to deferred treatment after a median of 5 years’ follow-up, children in the 40-week and 96-week group had their risk of death or treatment failure reduced by 40% and 50% respectively. Such findings further support the recent WHO guidelines which recommend starting ART in all infants who are suspected of having HIV. This data adds to the mounting number of clinical scenarios in which early ART in HIV appears to be favorable when compared to a delayed approach. [3]

While many interns are encountering patients with severe delirium for the first time this August, new evidence suggests that the most commonly used drug to help combat delirium may not be all that efficacious. Haloperidol, whose prior evidence was limited to small clinical trials showing reductions in duration of symptoms, has again been put to the test in this latest randomized control trial. Page et al randomized 142 patients in the ICU setting to receive either intravenous haloperidol 2.5mg every eight hours or normal saline with drug discontinuation occurring at the time of discharge, once the patient was delirium free or after a maximum of 14 days of treatment. The primary outcome assessed was number of delirium and coma-free days. Overall there was no difference in endpoint in either group, although those who received haloperidol were more likely to become over sedated. These findings suggest that within the first 14 days of treatment in an ICU setting, standing intravenous haloperidol is no better than placebo at reducing the number of delirium or coma-free days.[4]

Other interesting reads this week…

1.Csaba P. Kovesdy, Anthony J. Bleyer, Miklos Z. Molnar, Jennie Z. Ma, John J. Sim, William C. Cushman, L. Darryl Quarles, Kamyar Kalantar-Zadeh; Blood Pressure and Mortality in U.S. Veterans With Chronic Kidney DiseaseA Cohort Study. Annals of Internal Medicine. 2013 Aug;159(4):233-242. http://annals.org/article.aspx?articleid=1726794

Controlling blood pressure can be extremely difficult in those with chronic kidney disease. In a study investigating at a historical cohort from 2005 to 2012, Csaba et al showed that those with an ideal systolic blood pressure and diastolic blood pressure less than seventy mmHg had the highest mortality rates of all chronic kidney disease patients. Though not establishing causality, this study seems to suggest that the optimal blood pressure in those with chronic kidney disease may be between a systolic range of 130 to 159 and a diastolic range between 70 to 89 mmHg, with further reductions in blood pressure being associated with increased harm.

2. Tsoi KK, Hirai HW, Sung JJ. Meta-analysis: comparison of oral vs. intravenous proton pump inhibitors in patients with peptic ulcer bleeding. Aliment Pharmacol Ther. 2013 Aug 5. PubMed PMID: 23915096.  http://onlinelibrary.wiley.com/doi/10.1111/apt.12441/abstract

A new meta-analysis suggests that treating patients with oral proton pump inhibitors (PPI) in the setting of peptic ulcer bleeding may be equally as efficacious as treating with intravenous therapy. Pooled from six randomized trials, the majority of which were comprised of open labeled trials with limited sample sizes, the results showed that there was no difference in rates of recurrent bleeding, transfusion requirements, need to go to the operating room and all-cause mortality between the two therapies. Those, however, receiving oral PPI had a shorter length of hospital stay when compared to those receiving intravenous therapy. While the findings are interesting, they further support the need for a well-designed blinded randomized trial to see if oral therapy is as good as intravenous in the setting of acute peptic ulcer bleeding.

Dr. Brian Greet is the Chief Medical Resident at NYU Langone Medical Center

Peer reviewed by Matthew Vorsanger, MD, associate editor, Clinical Correlations

Image courtesy of Wikimedia Commons

References

[1] http://www.msf.org/article/syria-thousands-suffering-neurotoxic-symptoms-treated-hospitals-supported-msf

[2] Strbian D, Ringleb P, Michel P, Breuer L, Ollikainen J, Murao K, Seiffge DJ,Jung S, Obach V, Weder B, Eskandari A, Gensicke H, Chamorro A, Mattle HP, Engelter S, Leys D, Numminen H, Köhrmann M, Hacke W, Tatlisumak T. Ultra-Early Intravenous Stroke Thrombolysis: Do All Patients Benefit Similarly? Stroke. 2013 Aug 22. [Epub ahead of print] PubMed PMID: 23970791.  http://stroke.ahajournals.org/content/early/2013/08/22/STROKEAHA.111.000819.abstract

[3] Mark F Cotton, Avy Violari, Kennedy Otwombe, Ravindre Panchia, Els Dobbels, Helena Rabie, Deirdre Josipovic, Afaaf Liberty, Erica Lazarus, Steve Innes, Anita Janse van Rensburg, Wilma Pelser, Handre Truter, Shabir A Madhi, Edward Handelsman, Patrick Jean-Philippe, James A McIntyre, Diana M Gibb, Abdel G Babiker. Early time-limited antiretroviral therapy versus deferred therapy in South African infants infected with HIV: results from the children with HIV early antiretroviral (CHER) randomised trial. The Lancet. 2013 Aug 22. [Early Online Publication]  http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(13)61409-9/abstract

[4] Valerie J Page, E Wesley Ely, Simon Gates, Xiao Bei Zhao, Timothy Alce, Ayumi Shintani, Jim Jackson, Gavin D Perkins, Daniel F McAuley. Effect of intravenous haloperidol on the duration of delirium and coma in critically ill patients (Hope-ICU): a randomised, double-blind, placebo-controlled trial. The Lancet Respiratory Medicine. 2013 Aug 21. [Early Online Publication]  http://www.thelancet.com/journals/lanres/article/PIIS2213-2600(13)70166-8/abstract

 

 

Primecuts-This Week in the Journals

August 19, 2013

By: Kelly Forrester, MD

At Fenway Park on Sunday, after hitting a 6th inning home run that led the Yankees to a victory against the Red Sox, Alex Rodriguez made the ultimate statement to angry officials and fans that he is not going to give in.  Rodriguez has been under fire since January because of his ties to the Biogenesis baseball scandal where he was accused of using performance-enhancing drugs.  On August 5th, Rodriguez was suspended for 211 games, although he is allowed to play during his appeal process.  Last week, Rodriguez’s lawyer, Joseph Tacopina, claimed that the baseball commissioner is trying to wrongfully use Rodriguez as the “poster boy” for doping.  He also claimed that the Yankees are working with the commissioner to try to nullify Rodriguez’s contract.  Moving from the ballpark to the field of medicine…

“The resident 15”: A fear of every new intern as the dreaded consequence of long work hours and new stressors.  Unfortunately, a recent Nature Communications article proves what we have always suspected, that sleep deprivation increases the desire for high-calorie foods by altering the central nervous system’s regulation of dietary intake.  After deprivation of one night of sleep, study participants rated the desirability of 80 different food options and were told that they would subsequently be given whichever item they rated the highest.  While making their choices, functional magnetic resonance imaging (fMRI) scans measured their brain activity.  The study was then repeated seven days later using the same participants after receiving multiple nights of well-rested sleep averaging 8.2 hours a night.  The results showed that sleep deprivation diminishes activity in the regions of the frontal cortex and insular cortex involved in appetite evaluation while increasing activity in the amygdala.  The frontal and insular cortex are involved in assigning stimulus value and integrating food features that govern preferences, while the amygdala controls the motivation to eat, especially when the food is more desirable.  Participants also rated high-calorie food items more attractive after the night of sleep deprivation.  When correlating the fMRI results with the increased desire for weight-promoting food items in sleep-deprived participants, the findings suggest that weight gain associated with sleep deprivation is a result of decreased activity in the frontal cortex and excess activity in subcortical limbic regions.  Therefore, the next time you are on night float, try to elicit the help of your frontal cortex in choosing a salad over a pizza (1).

In other news this week, a New England Journal article re-analyzed the data from the 2003 Prostate Cancer Prevention Trial (PCPT) and found interesting results concerning the use of finasteride to prevent prostate cancer.  In the 2003 article, finasteride was found to reduce the relative risk of prostate cancer by 24% compared to placebo (2). However, finasteride also increased the rate of high-grade prostate cancer.  Despite subsequent analyses that showed that this increase was potentially caused by detection bias, the fear of increasing high-grade tumors has eliminated the use of finasteride in prostate cancer prevention.  The new study compared the risk of death among men treated with finasteride with men treated with placebo.  The assumption was that if finasteride actually increases the rate of high-grade prostate cancers, then there should be increased mortality in the finasteride group during long-term follow up.  The results showed that the 15-year rate of survival between the two groups was relatively similar and that there was no increase in the risk of death among men receiving finasteride (3). Although at first glance this makes finasteride seem like a wonderful primary prevention strategy, both groups in the study were regularly being screened for prostate cancer.  Given the recommendation from the United States Preventive Services Task Force (USPSTF) against screening for prostate cancer with prostate specific antigen (PSA), finasteride would have an undefined role in reducing the morbidity associated with the disease.  In addition, the study proved that it also has no role in decreasing mortality.  Perhaps the only use of finasteride is in men who choose to continue PSA testing despite current recommendations.

A recent article in The Lancet addressed another ubiquitous fear of healthcare workers: Clostridium difficile.  The study examined whether the probiotics lactobacilli and bifidobacteria help in prevention of antibiotic-associated diarrhea as well as its subset, C. difficile diarrhea, in older inpatients (the PLACIDE trial).  The results of previous meta-analyses, which have mostly supported the use of probiotics in preventing antibiotic-associated diarrhea, are controversial because of the variations in individual study designs and small sample sizes (4). The PLACIDE trial is a multicenter, randomized, double-blinded, placebo controlled trial with a sample size of 2,941 patients.  Patients aged 65 or older who had been treated with one or more oral or intravenous antibiotics in the previous seven days were given either a high-dose microbial preparation containing Lactobacillus acidophilus and bifidobacterium or a placebo pill.  The patients were then followed for 12 weeks.  Interestingly, the study found that there was no difference in antibiotic-associated diarrhea (including C. difficile associated diarrhea) between the two groups (95% CI 0.84-1.28, p=0.71) (5). Although probiotics do not appear to be useful in the prevention of antibiotic-associated diarrhea, clinicians may still decide to use them given their small risk of harm.

A JAMA article this week compared medical management versus early surgical intervention on the outcomes of asymptomatic mitral regurgitation from flail mitral valve leaflets.  Current controversy exists regarding the correct treatment choice for those without the American Heart Association guideline class I triggers, meaning no or minimal symptoms and no left ventricular dysfunction.  European recommendations favor medical management, or watchful waiting until a distinct event is encountered, whereas North American recommendations are in favor of early surgical intervention.  The primary endpoint of the study was all-cause mortality, and the secondary endpoints were heart failure and new-onset atrial fibrillation.  The study found that early surgical intervention, meaning within three months of diagnosis, was not associated with increased mortality or heart failure.  It was, however, associated with a small increase in new-onset atrial fibrillation.  Long-term results showed that early surgical correction was associated with a significant survival benefit and a decrease in heart failure risk (6). There was no difference in late-onset atrial fibrillation.  As for clinical decision making, it is still prudent to only refer patients to surgery if the surgical risk is low and the likelihood of valve repair success is high.

Other interesting articles:

1.  DeCamp, M., T. Koenig, and M. Chisolm. Social Media and Physicians’ Online Identity Crisis. JAMA.  August 14, 2013.  310(6): 581-582.

http://jama.jamanetwork.com/article.aspx?articleid=1728725

This editorial discusses how it is impossible for physicians to separate their professional and social media identities.  It rebels against the recommendations of the majority of medical organizations to maintain strict patient-physician boundaries online.  The article claims that it is not only operationally impossible, but it also induces psychological burden on physicians, is inconsistent with the wishes of active physician social media users, and it potentially instills patient distrust in their physicians.

2.  US Burden of Disease Collaborators.  The State of US Health, 1990-2010: Burden of Diseases, Injuries, and Risk Factors.  JAMA.  August 14, 2013.  310(6): 591-608.

http://jama.jamanetwork.com/article.aspx?articleid=1710486

In this study, researchers compared health outcomes in the USA with those of 34 other countries using data from the Global Burden of Disease Study 2010 (GBD 2010).  From 1990 to 2010, the US rank among the 34 other countries for age-standardized death rate changed from 18th to 27th.  The life expectancy at birth rank changed from 20th to 27th, and the healthy life expectancy (HALE) changed from 14th to 26th.  The age-specific rates of years lived with disability remained stable.

3.  Hsu-Wen, C., J. Wang, C. Chang, et al.  Risk of Severe Dysglycemia Among Diabetic Patients Receiving Levofloxacin, Ciprofloxacin, or Moxifloxacin in Taiwan.  Clinical  Infectious Disease.  August 14, 2013.

http://cid.oxfordjournals.org/content/early/2013/07/23/cid.cit439.abstract

Outpatient diabetic patients newly prescribed levofloxacin, ciprofloxacin, moxifloxacin, cephalosporins, and macrolides were monitored for dysglycemia for 30 days after initiation of antibiotic therapy.  The study found that diabetics are at increased risk for dysglycemia when using oral fluoroquinolones.  The risk of hypoglycemia was higher in those using moxifloxacin compared to levofloxacin and ciprofloxacin.

Kelly Forrester, MD is a first year internal medicine resident at NYU Langone Medical Center

Peer Reviewed by Matthew Vorsanger, MD, Associate Editor, Clinical Correlations

References:

1.  Greer, S., A. Goldstein, and M. Walker. The impact of sleep deprivation on food desire in the human brain. Nature Communications.  August 6, 2013.  4:2259.

2.  Thompson, I., P. Goodman, C. Tangen, et al.  The influence of finasteride on the development of prostate cancer.  The New England Journal of Medicine.  2003.  349:215-24.

3.  Thompson, I., P. Goodman, C. Tangen, et al. Long term survival of participants in the prostate cancer prevention trial. The New England Journal of Medicine.  August 15, 2013.  369:7.

4.  McFarland, LV.  Meta-analysis of probiotics for the prevention of antibiotic associated diarrhea and the treatment of Clostridium difficile disease.  American Journal of Gastroenterology.  2006.  101: 812–22.

5.  Allen, S., K. Wareham, D. Wang et al. Lactobacilli and bifidobacteria in the prevention of antibiotic-associated diarrhoea and Clostridium difficile diarrhoea in older inpatients (PLACIDE): a randomised, double-blind, placebo-controlled, multicentre trial. The Lancet. August 8, 2013. Epub ahead of print.

6.  Suri, R., J. Vanoverschelde, F. Grigioni et al. Association Between Early Surgical Intervention vs. Watchful Waiting and Outcomes for Mitral Regurgitation Due to Flail Mitral Valve Leaflets. JAMA.  August 14, 2013.  310(6):609-616.

 

Primecuts-This Week in the Journals

August 13, 2013

By: Theresa Sumberac, MD

What do the polio vaccine, in vitro fertilization, and gene mapping have in common? Their successes are all due, in varying extents, to the use of HeLa cells. HeLa cells were originally derived from a self-replicating cell line obtained unknowingly 65 years ago from Henrietta Lacks, a woman battling an aggressive form of cervical cancer. Researchers soon realized the potential of these cells, which have been referenced in over 74,000 studies to date. Concern by Ms. Lacks’ descendants erupted in the 1970’s when they were first alerted to the use of their ancestor’s cells for scientific research. However, since then, the family members have largely been ignored. The controversy was brought into the limelight again 5 months ago when the genome sequence for HeLa cells was published online. Ms. Lacks’ descendants were not informed of the project and were worried that information in the genome, such as the risk of Alzheimer’s disease or cancer, might be used in the future to discriminate against them. Working with the National Institute of Health, the Lacks family agreed to have the genome sequence stored in the NIH database where researchers could apply for access to the sequence. The request would be reviewed by a committee, including two members of the Lacks family. The agreement does not include any financial benefit from commercial products which may be developed by the research. The Immortal Life of Henrietta Lacks by Rebecca Skloot chronicles this unprecedented journey [1].

Meanwhile, a New England Journal article this week examined the effect of various glucose levels on the risk of developing dementia [2]. In a prospective cohort study involving volunteers of the Adult Changes in Thought (ACT) study group, 2067 dementia free community dwelling individuals over the age of 65 in Washington State were assessed every two years with the Cognitive Abilities Screening Instrument. Participants’ measurements of fasting glucose, random glucose, and glycosylated hemoglobin were combined using a hierarchical Bayesian framework to derive a time-varying estimate of the average glucose level for each participant at baseline and subsequent five year intervals. The participants were stratified into two groups based on whether or not they had diabetes (being defined as filling two diabetes related prescriptions per year). Over a median follow up of 6.8 years, dementia developed in 524 of 2067 (25.4%) total participants. In non-diabetics, 450 of 1724 (26.1%) developed dementia and in diabetics 74 of 343 (21.6%) developed dementia. The hazard ratio (HR) for dementia increased with increasing average glucose level in both groups. For an average glucose level of 115 in a patient without diabetes, the HR was 1.18 (95% CI 1.04-1.33, p= 0.01). An average glucose level of 190 in a patient with diabetes correlated with a HR of 1.40 (95% CI 1.12-1.76, p=0.002). These estimates were adjusted for confounding variables including age, sex, race, education, apoE ε4 allele, atrial fibrillation, hypertension, coronary artery disease, cerebrovascular disease, congestive heart failure, exercise, and smoking status. Baseline characteristics tended to favor increasing prevalence of confounders in the diabetic group although p values were not reported [2].

The limitations of this study included its prospective cohort design and the possibility of unknown confounders as well as the definition of diabetes used (filling two prescriptions a year of diabetes related medications). It is possible that individuals labeled as non-diabetics with higher glucose levels may have had undiagnosed diabetes. However, the authors contend that they found an increased risk for dementia even on the lower end of the glucose spectrum that was associated with rising glucose levels. This study highlights the importance of maintaining glycemic control in our patients with diabetes. However, the observation that higher levels of glucose increase dementia risk in individuals without diabetes underscores the need for further research into the mechanism by which this occurs, including the possibility that there may be an unknown confounder affecting results [2].

This week in JAMA, a randomized comparative effectiveness trial enrolled 5,994 uninsured men and women aged 54 to 64 to three different approaches for colorectal cancer screening [3]. Fecal immunochemical test (FIT) outreach involved mailing instructions and a free FIT card to the patient; colonoscopy outreach involved mailing an invitation to schedule a no-cost colonoscopy; and usual care involved routine primary care visit based screening. Both FIT and colonoscopy groups received up to two “live” telephone reminders within three weeks of the mailing and were allowed to continue usual care office based screening by their doctors. Screening participation rates for FIT were 40.7% (95% CI 38.3-43.1), colonoscopy 24.6% (95% CI 20.8-28.5), and usual care 12.1% (95% CI 11.1-13.1%), all with P<0.001. FIT and colonoscopy outreach were both superior to usual care with a number needed to treat to accomplish one additional screening over usual care of 8 for colonoscopy and 3.5 for FIT. FIT outreach was superior to colonoscopy outreach with regards to number of participants completing screening. However, 11 of 60 patients or 18% with abnormal FIT results did not subsequently undergo diagnostic colonoscopy. A limitation of the study was that it was conducted over only one year and cannot evaluate whether participants would continue to complete yearly FIT testing. Additionally, perhaps with continued yearly reminders, more patients would complete colonoscopy, making it a more preferred option than FIT, given that colonoscopy is more sensitive than FIT at detecting colorectal cancer. Given the results of this study, we may begin to see a change in public health efforts to screening for colorectal cancer using more mail outreach strategies and FIT technology. A cost benefit analysis is required to determine whether these new methods are feasible on a larger scale [3].

In Science this week, researchers reported an exciting development in the global health initiative to eliminate malarial infections worldwide [4]. Previous attempts at developing a vaccine have been unsuccessful. In a phase 3 efficacy trial published in 2012, the subunit vaccine RTS,S/AS01 was only able to prevent the development of malaria in 31.3% of African infants over a 12 month period[5]. As malaria infection is responsible for an estimated 0.66 to 1.24 million deaths worldwide, researchers press onward for a solution[4]. Now, in the results of a phase 1 clinical trial, intravenous administration of an irradiated whole sporozoite in the pre-erythrocytic stage in 5 doses resulted in immunity to subsequent challenge with malaria infection, with P=0.015 compared to controls. Control participants were individuals who did not receive the vaccine and were subsequently exposed to malaria infection. Adverse events included transient asymptomatic elevations in alanine aminotransferase and/or aspartate aminotransferase in 40% of vaccine recipients that was not dose dependent. Researchers postulate that the vaccine was successful since it was administered intravenously, which was more effective at eliciting T cell response in peripheral blood, especially in the liver. Future studies are needed to examine the duration of protection, optimal number and spacing of doses, and how to immunologically monitor response to the vaccine [4]. Once perfected, this vaccine would have a tremendous impact on global health worldwide, saving the lives of millions.

In the ongoing struggle to manage outpatient hypertension, both the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) and the American Heart Association recommend home blood pressure (BP) monitoring in addition to clinic visits for blood pressure evaluation despite a lack of supporting evidence [6, 7]. In the Annals this week, researchers conducted a systematic review and meta-analysis of 52 studies and found that self-monitored BP (SMBP) alone versus usual care (clinic blood pressure monitoring) had moderate strength evidence to lower blood pressure at 6 months with a summary net difference of -3.9mmHg systolic and -2.4mmHg diastolic blood pressure [8]. SMBP with support (defined as counseling, education, web-based, and miscellaneous) versus usual care had high strength evidence to decrease blood pressure for 12 months with systolic BP lowered by -3.4 to -8.9mmHg and diastolic BP lowered by -1.9 to -4.4mmHg. However, whether these effects last beyond 12 months is uncertain. Limitations include a lack of minority representation and patients other than those with uncomplicated hypertension [8]. Although the effects of blood pressure reduction are modest, at a population level this amount of reduction has been estimated to result in mortality reductions of 6% to 14% due to stroke, 4% to 9% due to chronic heart disease, and 3% to 7% due to all causes, making it a worthwhile consideration for individuals motivated to monitor their blood pressure at home [6, 9].

Additional Recommended Articles:

1. Goldfarb DS. A piece of my mind. Cocktail party nephrology. JAMA. 2013 Jun 26;309(24):2561-2.  Our own Dr. David Goldfarb reflects in his inimitable way on his personal experiences with nephrolithiasis and how it shaped his practice, including his current role as the director of a kidney stone clinic.

2. Lebwohl, B., et al., Mucosal healing and risk for lymphoproliferative malignancy in celiac disease: a population-based cohort study. Ann Intern Med, 2013. 159(3): p. 169-75.  In a population based cohort study, patients with celiac disease and persistent villous atrophy compared with mucosal healing on pathologic examination of intestinal biopsies were at increased risk for lymphoproliferative malignancy. Standardized incidence ratio (SIR), 3.78 (95% CI 2.71 to 5.12) with persistent villous atrophy and SIR, 1.50 (95% CI 0.77 to 2.62] with observed mucosal healing.

3. Vander Lugt, M.T., et al., ST2 as a marker for risk of therapy-resistant graft-versus-host disease and death. N Engl J Med, 2013. 369(6): p. 529-39.  Plasma levels of biomarker ST2 (suppression of tumorigenicity 2) in patients with graft versus host disease (GVHD) correlated with risk of developing treatment resistant disease or death after transplantation. Measurement of ST2 prior to treatment for GVHD and six months later could identify these individuals, allowing for closer monitoring and more aggressive therapy.

4. Li, C.I., et al., Use of Antihypertensive Medications and Breast Cancer Risk Among Women Aged 55 to 74 Years. JAMA Intern Med, 2013.  In a population based case-control study of women aged 55 to 74 years, exposure to any type of calcium channel blocker for more than ten years was associated with an increased risk of ductal breast cancer (OR 2.4, 95%CI 1.2-4.9, P = .04) and lobular breast cancer (OR 2.6, 95%CI 1.3-5.3, P = .01). There was no appreciated increased risk with other types of antihypertensives including diuretics, beta-blockers, and angiotensin II inhibitors. Further research, including prospective studies, are required to further evaluate this finding before practice changing recommendations can be made.

Theresa Sumberac, MD is a third year internal medicine resident at NYU Langone Medical Center

Peer Reviewed by Matthew Vorsanger, MD, Associate Editor, Clinical Correlations

References:

1. Zimmer C. A Family Consents to a Medical Gift, 62 Years Later. The New York Times August 7,2013.

2. Crane, P.K., et al., Glucose levels and risk of dementia. N Engl J Med, 2013. 369(6): p. 540-

3. Gupta, S., et al., Comparative Effectiveness of Fecal Immunochemical Test Outreach, Colonoscopy Outreach, and Usual Care for Boosting Colorectal Cancer Screening Among the Underserved: A Randomized Clinical Trial. JAMA Intern Med, 2013.

4. Seder, R.A., et al., Protection Against Malaria by Intravenous Immunization with a Nonreplicating Sporozoite Vaccine. Science, 2013.

5. Agnandji, S.T., et al., A phase 3 trial of RTS,S/AS01 malaria vaccine in African infants. N Engl J Med, 2012. 367(24): p. 2284-95.

6. Chobanian, A.V., et al., The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. Jama, 2003. 289(19): p. 2560-7

7. Pickering, T.G., et al., Call to action on use and reimbursement for home blood pressure monitoring: Executive Summary. A joint scientific statement from the American Heart Association, American Society of Hypertension, and Preventive Cardiovascular Nurses Association. J Clin Hypertens (Greenwich), 2008. 10(6): p. 467-76.

8. Uhlig, K., et al., Self-Measured Blood Pressure Monitoring in the Management of Hypertension: A Systematic Review and Meta-analysis. Ann Intern Med, 2013. 159(3): p. 185-94.

9. Whelton, P.K., et al., Primary prevention of hypertension: clinical and public health advisory from The National High Blood Pressure Education Program. Jama, 2002. 288(15): p. 1882-8.

 

 

 

Primecuts-This Week in the Journals

August 6, 2013

By: Matthew Weiss, MD

Though Don Draper publicly explained to us “Why I’m Quitting Tobacco” as far back as 1965, we’re still collectively dealing with the repercussions of those smokers, Don included, who didn’t follow his sage advice. Lung cancer today, 85% of which is attributable to cigarette use, makes up more than a quarter of all cancer deaths and claims roughly 160,000 American lives yearly – more than the toll from colorectal, breast and prostate cancers combined [1]. Nearly 90 percent of patients with lung cancer ultimately die from it, but perhaps often because it is diagnosed “too late.”

For decades now doctors have been struggling to succeed in guiding their patients to quit – or better yet, to not start – smoking. All too frequently that message seems to fall on deaf ears, and instead the main medical objective becomes not one of primary prevention but one of treatment of frank disease. In the 1970s the American Cancer Society recommended chest X-rays as a screening modality to diagnose “early” lung cancer, but that recommendation was ultimately withdrawn in 1980 after it was concluded to have insufficient evidence for improved mortality [2]. This week the tide is again turning for lung cancer screening as the United States Preventive Services Task Force (USPSTF) has tentatively formalized a new recommendation to screen “high risk” patient populations with low-dose computed tomography (LDCT) scans [3,4].

The basis for this recommendation comes from a new report published this week in the Annals of Internal Medicine [5]. With the goal of updating the USPSTF, which last addressed the screening issue in 2004 and does not currently endorse chest X-ray or CT screening, this group of researchers sifted through over 8,000 abstracts and 67 full-text articles which addressed the issue [6]. Ultimately they focused on four trials in particular which they deemed to best assess the effectiveness of LDCT [7-11]. Of those four studies, two in particular showed reduced lung cancer related mortality with LDCT use, while two other studies, which the group deemed of “fair or poor quality” and less applicable to American populations, did not. The current group focused most closely on the National Lung Screening Trial (NLST) from 2011, which compared three annual LDCTs versus conventional chest x-rays in 50,000 patients aged 55-74 with smoking histories of greater than 30 pack-years. The current group emphasized the findings of the NLST, namely that after 6.5 years of follow-up, lung cancer mortality was reduced by 20% (95% CI, 6.8% to 26.7%) in the LDCT group with a number needed to screen (NNS) to prevent one lung cancer death of 320. Additionally, all-cause mortality was reduced by 6.7% with NNS of 219 [11]. Of note, these numbers compare favorably with other, now standard–of-care, screening practices – NNS via mammography to prevent once breast cancer death being 1339 for women 50-59 after up to 20 years of follow-up; as well as the NNS via flexible sigmoidoscopy of 817 for colon cancer related death [12-14].

The results of this review and the USPSTF’s new recommendation have major implications for patients and the healthcare system as a whole, however there are some significant gaps. None of the newest analysis specifically addressed gender, racial or ethnic groups, nor did it address the issue of radiation exposure via repeated CT scans. A USPSTF recommendation carries with it major financial implications, including payment coverage by most insurances (including Medicare), but again the studies to date did little to address the screening issues of overdiagnosis and false-positive related anxiety. While a “free” screening LDCT may comfort many patients with a strong smoking history, will the risk of a false-positive or frequent radiation exposure push them to a cigarette to ease their anxiety?

Last week offered an interesting case from the NYU intensive care unit of a 70 year-old woman presenting with hypotension in the setting of three weeks of watery diarrhea with an unrevealing initial workup. A concomitant report from the New York City Department of Health and Mental Health suggested NYC medical providers be on the alert for exactly such cases in the setting of a nationwide outbreak of cyclosporiasis, a protozoal disease notably not routinely tested for on laboratory ova and parasites (O+P) tests [15]. Currently 400 cases have been reported (41 confirmed) within the 16 states and 22 patients hospitalized. As of this week the CDC and FDA have issued a traceback investigation report confirming at least two Iowa and Nebraska cases as secondary to pre-packaged salad dressing contaminants. The source appears to be a food services company by the name of Taylor Farms de Mexico which supplies restaurants including Red Lobster and Olive Garden. Unlimited salad bar? No thanks. Of educational note, this report should refresh the practitioner’s memory of cyclospora, a fecal-orally transmitted human intracellular protozoal parasite capable of causing a typically self-limited diarrheal illness sometimes associated with generalized symptoms. Diagnostic screening requires a modified acid fast stain, not always included as part of the standard O+P. Typical treatment course involves a seven-day course of oral trimethoprim-sulfamethoxazole.

A new meta-analysis from the British Medical Journal reassesses the current 2009 European Society of Cardiology (ESC) class I recommendation regarding perioperative initiation of beta-blockade in those at risk for cardiac events undergoing high- or intermediate- risk surgery or vascular surgery [16]. Prior pro-beta-blocker data and recommendations stem largely from the DECREASE family of studies first published in 1999 and now much discredited secondary to the lead author’s well publicized violations of academic integrity [17,18]. The latest meta-analysis includes 10,000 patients in nine randomized controlled trials (DECREASE excluded) of initiation of beta-blockers before non-cardiac surgery. Findings show that initiation of a course of beta-blockers before surgery caused a 27% risk increase in 30-day all-cause mortality (p=0.04). Subgroup analysis found that while beta-blockade reduced non-fatal myocardial infarction (RR 0.73, p=0.001), risk of stroke and hypotension were increased (RR 1.73, p=0.05 and RR 1.51, p<0.00001, respectively). This data has major implications within the U.S. and especially in Europe where perioperative beta-blockers are still routinely recommended per the ESC 2009 guidelines.

Lastly, the British Medical Journal reports new data from a meta-analysis which combined six studies with roughly 900,000 type-2 diabetic patients who experienced severe hypoglycemia in non-acute hospital setting to assess the associated risk of cardiovascular disease [19]. All studies reviewed showed a strong positive association between hypoglycemia and cardiovascular disease (RR 1.60 to 3.45). Traditionally the association between hypoglycemia and worsened cardiovascular outcomes has been attributed to comorbid illness. However, further analysis to eliminate confounding from unmeasured comorbid severe illnesses (renal and liver disease, etc.) suggests that these illnesses may not explain the observed association between severe hypoglycemia and cardiovascular disease. Suggested physiologic explanations include catecholamine response, increased platelet activation, leukocyte mobilization and subsequent coagulation with resulting adverse effects on the myocardium and vascular system as a result of hypoglycemia. This meta-analysis suggests the story may be more straightforward with a possible direct correlation between hypoglycemia and adverse cardiovascular events. This data adds to the already known risks of intense glucose control established in the ACCORD trial where strict glycemic control goals led to a 22% increase in total mortality [20] and suggests more moderate goals for glycemic control in patients with type-2 diabetes.

Also interesting in the journals recently…

1. Iglehart J. The Residency Mismatch. N Engl J Med. July, 25 2013. 369;4. http://www.nejm.org/doi/full/10.1056/NEJMp1306445.  A new Perspective piece from the New England Journal points to the growing disparity between the number of students receiving medical education within the United States and the number of Graduate Medical Education positions available for residency training suggesting that “it may soon be impossible for all graduates of U.S. medical and osteopathic colleges to secure GME slots.”

2. Agnieszka P. Knowledge about heart failure in primary care: Need for strengthening of continuing medical education. Cardiology Journal. Vol 20, No 4, 2013. http://czasopisma.viamedica.pl/cj/article/view/CJ.2013.0093 .  Also with regard to medical education, a new study from Poland suggests that general practitioner age is inversely proportional to appropriate outpatient management of heart failure. Older physicians were more likely to point to electrocardiogram and chest films as exclusion criteria for systolic heart failure and were less likely to prescribe angiotensin receptor blockers and beta blockers, instead preferring spironolactone and digitalis while younger physicians opted for newer beta blockers such as carvedilol (p<0.05).

3. Sabayan B. Association of visit-to-visit variability in blood pressure with cognitive function in old age: prospective cohort study. BMJ 2013; 347. http://www.bmj.com/content/347/bmj.f4600 . New data from a prospective study of 5,000 patients of mean age 75 who were at risk for cardiovascular disease suggests that high variability in blood pressure, independent of mean blood pressure (as measured from visit-to-visit) was associated with impaired cognitive function. The magnitude of the association was similar to the observed differences between groups of apolipoprotein E genotype positive patients where it has been shown that people who carry this risk factor for dementia have a four-times higher risk of developing late onset Alzheimer’s disease. Further study is warranted to determine if reduced variability in BP might decrease the risk of cognitive impairment in old age.

Matthew Weiss, MD is a second year resident at NYU Langone Medical Center

Peer Reviewed by Matthew Vorsanger, MD, Associate Editor, Clinical Correlations

References

1. American Cancer Society. Cancer Facts & Figure 2013. Atlanta, GA: American Cancer Soc; 2013. http://www.cancer.org/research/cancerfactsstatistics/allcancerfactsfigures/index .

2. Eddy D. ACS report on the cancer-related health checkup. CA Cancer J Clin. 1980; 30: 193-240. http://www.ncbi.nlm.nih.gov/pubmed/6774802?dopt=Abstract .

3. Tavernise S. Task Force Urges Scans for Smokers at High Risk. The New York Times. July, 29 2013. http://www.nytimes.com/2013/07/30/health/task-force-recommends-screening-for-heavy-smokers.html.

4. Panel Backs Lung Cancer Screening for Some Smokers. The Associated Press via NPR. July, 29 2013. http://www.npr.org/templates/story/story.php?storyId=206764757 .

5. Humphrey L. Screening for Lung Cancer with Low-Dose Computed Tomography: A Systematic Review to Update the U.S. Preventive Services Task Force Recommendation. Ann Intern Med. July, 30 2013. http://annals.org/article.aspx?articleid=1721248 .

6. U.S. Preventive Services Task Force. Lung cancer screening: recommendation statement. Ann Intern Med. 2004; 140:738-9. http://annals.org/article.aspx?articleid=717423 .

7. Infante M. A randomized study of lung cancer screening with spiral computed tomography: three-year results from the DANTE trial. Am J Respir Crit Care Med. 2009;180:445-53. http://www.atsjournals.org/doi/abs/10.1164/rccm.200901-0076OC .

8. Infante M. Lung cancer screening with spiral CT: baseline results of the randomized DANTE trial. Lung Cancer. 2008;59:355-63. http://www.lungcancerjournal.info/article/S0169-5002(07)00511-9/abstract .

9. Saghir Z. CT screening for lung cancer brings forward early disease. The randomized Danish Lung Cancer Screening Trial: status after five annual screening rounds with low-dose CT. Thorax. 2012;67:296-301. http://thorax.bmj.com/content/67/4/296.abstract .

10. Pastorino U. Annual or biennial CT screening versus observation in heavy smokers: 5-year results of the MILD trial. Eur J Cancer Prev. 2012;21:308-15. http://journals.lww.com/eurjcancerprev/Abstract/2012/05000/Annual_or_biennial_CT_screening_versus_observation .15.aspx.

11. Aberle DR. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med. 2011; 365:395-409. http://www.nejm.org/doi/full/10.1056/NEJMoa1102873 .

12. Humphrey L. Breast cancer screening: a summary of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med. 2002;137:347-60. http://annals.org/article.aspx?articleid=715608 .

13. Nelson H. Screening for Breast Cancer: Systematic Evidence Review Update for the U.S. Preventive Services Task Force. Rockville, MD: Agency for Healthcare Research and Quality; 2009. Report 10-05142-EF-1. http://annals.org/article.aspx?articleid=745247 .

14. Schoen R. Colorectal-cancer incidence and mortality with screening flexible sigmoidoscopy. N Engl J Med. 2012;336:2345-57. http://www.nejm.org/doi/full/10.1056/NEJMoa1114635 .

15. NYC DOHMH. Nationwide Outbreak of Cyclosporiasis. http://cdc.gov/parasites/cyclosporiasis/outbreaks/investigation-2013.html .

16. Bouri S. Meta-analysis of secure randomized controlled trials of B-blockade to prevent perioperative death in non-cardiac surgery. Heart. Published Online First: July 31, 2013. http://heart.bmj.com/content/early/2013/07/30/heartjnl-2013-304262.abstract .

17. Poldermans D. The Effect of Bisoprolol on Perioperative Mortality and Myocardial Infarction in High-Risk Patients Undergoing Vascular Surgery. N Engl J Med 1999; 341:1789-1794. http://www.nejm.org/doi/full/10.1056/NEJM199912093412402 .

18. Erasmus MC fires Poldermans; ESC reviews his work. http://www.theheart.org/article/1315171.do .

19. Atsushi G. Severe hypoglycemia and cardiovascular disease: systematic review and meta-analysis with bias analysis. BMJ 2013, July 30. http://bmj.com/content/347/bmj.f4533 .

20. Gerstein HC. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008;358:2545-59. http://www.nejm.org/doi/full/10.1056/NEJMoa0802743 .

 

 

Primecuts – This Week In The Journals

July 29, 2013

By Arnab Ghosh, MD

Faculty Peer Reviewed

This week’s Clinical Correlations begins with news from across the ‘pond’ and the much-anticipated birth of Prince George of Cambridge. The third in line to crown of the English monarchy, behind his grandfather Prince Charles and father Prince William the Prince George, George Alexander Louis was born on the 22rd of July 2013. The last use of the name, commonly represented in the history of the British monarchy, was by the Queen’s father, King George VI. It is understood that the use of the name ‘George’ paid homage to the Queen’s father (1). Since the wedding of the Prince William and Kate Middleton, the popularity of the British crown has increased, representing a shift in sentiments directed towards the British monarchy both in Britain and abroad.

Returning back to the USA, a number of interesting studies were published this week. The debate about the use of digoxin in heart failure was again raised in an article published in the American Journal of Medicine (2). Researchers from the Digitalis Investigation Group (DIG) trial examined the role of digoxin in reducing hospital readmission rates for Medicare patients (>65 years old) with known systolic heart failure. Readmission rates have become particularly pertinent in this new cost-conscious climate with hospitals soon being penalized for readmissions of patients with heart failure under the Affordable Care Act.

Using the original data from the DIG trial, this double blinded, placebo-controlled randomized trial looked at the effect of digoxin in 3405 patients (mean age 72 years, 25% women and 89% white) with LV ejection fractions on average 29%, (76% of which were secondary to ischaemic cardiomyopathy). The majority (85-87%) of patients were New York Heart Association Class II or III across the control and experimental group and nearly all the studied patients were on ACE inhibitors (94%) and diuretics (82%).

The results showed that there was a statistically significant reduction in all-cause readmissions at 30 days (HR = 0.66, 95% CI 0.51-0.86, p = 0.002), cardiovascular-related readmissions at 30 days (HR = 0.53, 95% CI 0.38-0.72, p < 0.001) and heart failure readmissions at 30 days (HR = 0.4, 95% CI 0.26-0.62, p < 0.001). Of note, 30 day mortality rates (all cause, cardiovascular and heart failure specific causes) were not significant. A noticeable confounder explaining these results was the potential effect of increased healthcare involvement to monitor the effects of digoxin (including drug levels). Also, in this study use of aldosterone antagonists nor beta-blockers was not reported. Another limitation included the homogenous study sample of predominately white males, which makes it harder to extrapolate to other populations of patients.

Nonetheless, with digoxin falling out of favor with many clinicians in the treatment of heart failure, these findings remind us of the value of this drug in reducing readmission rates, if not mortality. This data suggests that the ongoing difficulty in using digoxin in patients with underlying renal dysfunction and also its monitoring should not dissuade clinicians from using this medication.

In concert with last week’s discussion in Clinical Correlations, the disparities in healthcare between races remain a regrettable but important facet of the US healthcare system. In a study examining data from the National HIV Surveillance System of the CDC and the Medical Monitoring Project, Hall et al (2) investigated the differences in HIV care, particularly the continuum of care, by sex, age, race and ethnicity over 2009

Among the population estimated to have HIV, 44% were African-American, 19% Hispanic/Latino and 33% white. 76% were male, and 52% of the male population with HIV attributed it to MSM contact. More concerning was that of those living with HIV only 66% were linked with care (defined as having at least 1 report of CD4 count or viral load within 3 months of diagnosis), 37% remained in care, 33% were prescribed antiretrovirals and 25% had a suppressed viral load. Ethnic differences were noted across the spectrum of HIV care, with African-Americans consistently less linked to care than whites, with this approaching statistically significant (white to African-American, p=0.07, white to Hispanic/Latino, p=0.51).

Patients between the age groups 25-34 years and 35-44 years were less linked with care as compared to patents between 45-54 (p <0.001). Given this data, the importance of performing HIV tests on individuals with risk factors cannot be understated, particularly in younger patient populations of Hispanic and African-American ethnic groups less likely to seek care.

For patients with rheumatoid arthritis (RA), the drug methotrexate remains the cornerstone of treatment. In the event that this alone should fail, often clinicians use biological agents such as TNF alpha inhibitors to augment treatment over other drug-modifying anti-rheumatoid arthritis drugs (DMARDs). However the cost of TNF alpha medications remains an issue. Furthermore, a comparison of other immunosuppressive agents with biological in methotrexate-treatment failure RA has not been undertaken. To assess this, this week’s New England Journal of Medicine published an article by O’Dell et al (4) comparing the two types of treatment. The researchers compared the triple therapy of methotrexate, sulfasalazine (maximum 2g daily) and hydrochloroquine (400mg daily) to the double therapy etanercept (weekly)/methotrexate in a double-blinded non-inferiority trial comparing over 48 weeks in 353 patients who failed methotrexate therapy with 15-25mg weekly for at least 12 weeks.

The primary outcome used to assess for non-inferiority was a change in the Disease Activity Score for 28 joints (a standardized score representing composite number of physical examination findings, pain scores and lab values such as ESR) at 48 weeks. Using a non-inferiority margin of less than 0.6 point difference in DA28 score, at 48 weeks the triple therapy was found to be non-inferior compared with the double therapy of etanercept/methotrexate (p for non-inferiority = 0.002) according to a per-protocol analysis.

Twelve patients discontinued all therapy in the triple therapy group, whereas 5 discontinued in the double therapy group, and there were more serious infections in the double therapy group (12, with one death) compared to the triple therapy group (4, no deaths). Major limitations of the study include the use of a conservative non-inferiority margin, owing in part to the lack of enrolment, which in turn limited the power of the study.  In addition there was a the large number of men, who are thought to have a better biological response to treatment compared with women. While this data suggests there is no significant difference between the triple and double therapy for methotrexate-failed RA, clinicians need to be mindful of the risk of infection with TNF-alpha combinations, given the risk of serious immunosuppression.

With almost 19 cents in every dollar spent going to healthcare in the United States, controlling the cost of care remains an important goal. With this in mind, physicians’ views about cost control and physician responsibility were assessed in a study published by JAMA this week (5). 2556 physicians were surveyed for their views around three major topics: 1) the perceived role of the physician in controlling costs; 2) enthusiasm for cost-containment strategies and 3) the professional role in cost containment

Of note, respondents noted that most major stakeholders (health insurance companies, hospitals, patients) had a role in reducing costs, while noted than 36% thought physicians had a major role in reducing health costs. Furthermore, enthusiasm to reduce costs was high amongst physician respondents, (75% very enthusiastic) but there was a schism between adherence to clinical guidelines to reduce costs (76%) and ‘being solely devoted to…patient’s best interests, even if that is expensive’ (78%). This data underlines the fundamental tension between the social responsibilities of physicians to contain costs with the individual responsibility to deliver optimal care to their patients

Other articles of note:

Jacobson MF, Havas S, McCarter R. Changes in sodium levels in processed and restaurant foods, 2005 to 2011. JAMA Intern Med. 2013;173(14):1285-91

This retrospective cross-sectional analysis looked at sodium content in processed and restaurant foods according to the data from the Center for Science in the Public Interest. It was noted that there was a 3.5% decline in sodium content in processed food whereas in fast-food restaurants, sodium content increased by 2.6%

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Baron E, Miller M, Weinstein M et al. A Guide to Utilization of the Microbiology Laboratory for Diagnosis of Infectious Diseases: 2013 Recommendations by the Infectious Diseases Society of American (IDSA) and the American Society for Microbiology (ASM). Clin Inf Dis 2013;57(4):485-488

This report released by the Infectious Disease Society of America outlines the common pitfalls and issues with collection microbiological data, including many common sense interventions such as appropriate and accurate labeling of microbiological tests and specimen collection prior to antibiotic administration.

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Aggarwal B, Ellis SG, Lincoff AM et al. Cause of Death Within 30 Days of Percutaneous Coronary Intervention in an Era of Mandatory Outcome Reporting. J Am Coll Cardiol. 2013 May 8. doi:pii: S0735-1097(13)01787-7. 10.1016/j.jacc.2013.03.071

This article noted the findings on causes and incidence of 30-day mortality in relation to percutaneous coronary intervention (PCI) in a retrospective analysis of registry data. It showed overall prevalence of all-cause mortality of 2% (n=81) out of a total of 2078 PCIs. Of those who died, 58% were from cardiac causes (72% of which were PCI-related, most commonly periprocedural bleeding), and 42% from non cardiac causes (the most common being septic shock and stroke).

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Ghofrani H, D’Armini A, Grimminger F et al. Riociguat for the Treatment of Chronic Thromboembolic Pulmonary Hypertension. NEJM. 2013;369(4):319-329)

This was a industry-funded, placebo controlled randomized multicenter double blinded study comparing riociguat ( a souble guanylate cyclase stimulator) in patient with chronic thromboembolic pulmonary hyerptension using functional status (6 min walk test) as the primary outcome. It showed a significant decrease in the 6 min walk test compared to placebo.

Dr. Arnab Ghosh is a 2nd year resident at NYU Langone Medical Center

Peer reviewed by Neil Shapiro, MD, Editor-In-Chief, Clinical Correlations

Image courtesy of Wikimedia Commons

References:

(1) Burn J. The Little Prince Gets a Name: George. The New York Times July 24th, 2013 http://www.nytimes.com/2013/07/25/world/europe/and-the-name-isgeorge-alexander-louis.html?_r=0

(2) Bourge R, Fleg J, Fonarow G et al. Digoxin Reduces 30-day ALL-cause Hospital Admission in Older Patients with Chronic Systolic Heart Failure. Am J Med. 2013;126(8): 701-708

(3) Hall HI, Frazier EL, Rhodes P et al. Differences in human immunodeficiency virus care and treatment among subpopulations in the United States. JAMA Intern Med. 2013;173(14):1337-44.  http://archinte.jamanetwork.com/article.aspx?articleid=1697789

(4) O’Dell J, Mikuls T, Taylor T et al. Therapies for Active Rheumatoid Arthritis after Methotrexate Failure. NEJM. 2013;369(4):307-318  http://www.ncbi.nlm.nih.gov/pubmed/23755969

(5) Tilburt J, Wynia M, Sheeler R. Views of US Physicians About Controlling Health Care Costs. JAMA 2013;310(4):380-388 http://jama.jamanetwork.com/article.aspx?articleID=1719740&utm_source=Silverchair%20Information%20Systems&utm_medium=email&utm_campaign=MASTER%3AJAMALatestIssueTOCNotification07%2F23%2F2013

(6) Jacobson MF, Havas S, McCarter R. Changes in sodium levels in processed and restaurant foods, 2005 to 2011. JAMA Intern Med. 2013;173(14):1285-91  http://archinte.jamanetwork.com/article.aspx?articleid=1687516

(7) Baron E, Miller M, Weinstein M et al. A Guide to Utilization of the Microbiology Laboratory for Diagnosis of Infectious Diseases: 2013 Recommendations by the Infectious Diseases Society of American (IDSA) and the American Society for Microbiology (ASM). Clin Inf Dis 2013;57(4):485-488  http://cid.oxfordjournals.org/content/early/2013/06/24/cid.cit278.full.pdf

(8) Aggarwal B, Ellis SG, Lincoff AM et al. Cause of Death Within 30 Days of Percutaneous Coronary Intervention in an Era of Mandatory Outcome Reporting. J Am Coll Cardiol. 2013 May 8. doi:pii: S0735-1097(13)01787-7.   10.1016/j.jacc.2013.03.071  https://www.ncbi.nlm.nih.gov/m/pubmed/23665371/?i=6&from=/18215596/related

(9) Ghofrani H, D’Armini A, Grimminger F et al. Riociguat for the Treatment of Chronic Thromboembolic Pulmonary Hypertension. NEJM. 2013;369(4):319-329  http://www.nejm.org/doi/full/10.1056/NEJMoa1209657

Primecuts – This Week In The Journals

July 22, 2013

By Mark Adelman, MD

Faculty Peer Reviewed

In the wake of George Zimmerman’s acquittal this past week for the shooting death of Trayvon Martin, rallies and marches continue around the country to protest perceived racial inequalities in the criminal justice system. President Obama spoke on Friday in an unusually personal manner regarding the experiences of young African American men. Summing up his views by stating, “Trayvon Martin could have been me 35 years ago,” Obama urged more frank, open discussions about the history and future of race relations in America.

Racial disparities have also been well described in the realm of healthcare. The National Center for Health Statistics, a part of the CDC, recently released a report that described trends in causes of death and life expectancy that differ between white and black Americans (1). Comparing the years 1970 and 2010, the authors found an overall increase in life expectancy among the total US population from 70.8 years to 78.7 years. However, the average life expectancy remains higher for whites than blacks (78.9 years vs. 75.1 years in 2010). Encouragingly between 1970 and 2010, this gap in life expectancy has decreased from 7.6 years to 3.8 years, but the disparity is still present. In 2010, black Americans had higher mortality rates due to heart disease, cancer, homicide, diabetes mellitus and perinatal conditions, which collectively accounted for 60% of the black population disadvantage in life expectancy. These data should serve to remind clinicians and public health stakeholders that interventions targeting the management of cardiovascular risk factors, screening for preventable cancers, the epidemic of gun violence, and infant mortality could be of particularly high yield in further eliminating racial disparities in US life expectancy.

The actor Michael Douglas made headlines last month in an interview when he attributed his throat cancer diagnosis to human papillomavirus infection contracted by performing oral sex (2). HPV infection, particularly with serotype 16, is known to cause a subset of oropharyngeal cancers (3). Vaccinating adolescent females against oncogenic strains of HPV associated with cervical cancer has been shown to reduce the prevalence of infection with those strains (4). Investigators in Costa Rica working with the National Cancer Institute published their findings this week on the impact of vaccination with bivalent HPV16/18 vaccine on oral HPV infections. In this study, 7,466 sexually active 18-25 year old women in two areas of Costa Rica were randomized in a blinded fashion to receive HPV16/18 or hepatitis A vaccines. Subjects were given booster doses and followed for four years with annual pap smears and HPV DNA testing of cervical samples, and at the fourth-year visit gave oral specimens that were analyzed for HPV DNA. Among 5,834 women that completed follow-up, the investigators estimated a 93% type-specific (HPV16/18) vaccine efficacy rate; there was one infection with either of these strains in the vaccine group vs. 15 in the control group. A major limitation of the study was that it was initially designed primarily to study the vaccine’s effect on cervical HPV infection, so oral specimens were obtained only at the study’s conclusion, unlike cervical specimens which were collected at baseline and throughout the four years of follow-up. This made it impossible to measure the incidence of oral infections in the vaccine and control groups. However these results do add to the body of evidence that HPV vaccination effectively reduces the risk of infection with oncogenic strains of HPV at different body sites and will hopefully reduce the future burden of cervical, oropharyngeal and anal cancers.

Another study of interventions that may prevent cancer–in this case of the colon and rectum–was published in this week’s Annals of Internal Medicine (5). This was a long-term observational follow-up study of former participants in the Women’s Health Study, a large randomized controlled trial that investigated aspirin and vitamin E for the primary prevention of various cancers and cardiovascular disease that enrolled nearly 40,000 women between 1993 and 2004. About 34,000 women agreed to continue participating for a median follow-up of 18 years. Long-term low-dose aspirin use (100mg every other day) was associated with a reduced risk of developing colorectal cancer (HR 0.80; P=0.021) but not breast or lung cancers. Kaplan-Meier curves suggested that the difference between groups emerged after 10 years of treatment. Not surprisingly, aspirin users had higher rates of gastrointestinal bleeding (HR 1.14; P<0.001). We should consider aspirin use for women at higher risk of developing colorectal cancer but the risk of precipitating GI bleeds would likely limit its use among otherwise healthy women.

The increasing prevalence of obesity in the US has been labeled by many as an epidemic. The AMA went so far as to label obesity a disease during its annual meeting in Chicago last month, noting its relationship to hypertension and type 2 diabetes with their associated cardiovascular morbidity and mortality (6). This week in JAMA, further results of the CARDIA (Coronary Artery Risk Development in Young Adults) study were published (7). In this study, nearly 3300 non-obese adults aged 18 to 30 were followed for up to 25 years, with serial measurements of BMI and waist circumference every few years as well as measurement of coronary artery calcification by CT at either 15, 20 or 25 year follow-up visits. Longer duration of obesity was associated with increased presence and severity of coronary artery calcifications (P<0.001 for both). In addition, 38.2% and 39.3% of participants with more than 20 years of overall and abdominal obesity, respectively, had coronary artery calcifications, vs. 25% in participants who did not become obese. Although the study did not include any hard cardiovascular outcomes, coronary artery calcifications are associated with risk of coronary artery disease (8). The correlation found between duration of obesity and severity of coronary artery calcifications is especially concerning given the high rates of obesity among children in the US.

Other articles of note:

Mancia G, Bombeli M, Brambilla G. Long-Term Prognostic Value of White Coat Hypertension: An Insight From Diagnostic Use of Both Ambulatory and Home Blood Pressure Measurements. Hypertension. 2013;62:168-174.  http://hyper.ahajournals.org/content/62/1/168

2051 residents of a town in Italy each underwent three different forms of blood pressure measurement: in-office, self-measured at home, and 24 hour ambulatory monitoring. Participants were labeled as having white coat hypertension if their in-office BP was elevated but at least one out-of-office BP was normal. Those with normal BPs on both out-of-office measures were considered to have true white coat hypertension, while those with an elevated BP on one of the out-of-office measures had partial white coat hypertension. After an average 16 years of follow-up, cardiovascular and all-cause mortality were higher among patients with sustained hypertension and partial white coat hypertension, but not true white coat hypertension, when compared to normotensive participants.

Jamal SA, Vandermeer B, Raggi P et al. Effect of calcium-based versus non-calcium-based phosphate binders on mortality in patients with chronic kidney disease: an updated systematic review and meta-analysis. Lancet. Early online publication. doi:10.1016/S0140-6736(13)60897-1.  http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2813%2960897-1/abstract

This systematic review included 11 randomized trials that compared mortality in chronic kidney disease patients taking calcium-based phosphate binders with those taking non-calcium based binders. Patients taking non-calcium based binders had a 22% relative reduction in all-cause mortality compared to those taking calcium-based binders.

Atar S, Wishniak A, Shturman A, Shtiwi S, Brezins M. Fatal Association of Mechanical Valve Thrombosis With Dabigatran: A Report of Two Cases. Chest. 2013;144(1):327-328.  http://journal.publications.chestnet.org/article.aspx?articleid=1699501

The authors present two cases of patients with mechanical mitral valves who were switched from warfarin to dabigatran and within 2-3 months both experienced severe thrombotic complications leading to their deaths. Cases like these should serve as a reminder that the novel oral anticoagulants are not FDA approved for thromboprophylaxis in patients with mechanical valves, and no randomized data have been published establishing their efficacy or safety in these patients.

Dr. Mark Adelman is a 3rd year resident (Medicine) at NYU Langone Medical Center

Peer reviewed by Matthew Vorsanger, MD, Associate Editor, Clinical Correlations

Image courtesy of Wikimedia Commons

References:

1. Kochanek KD, Arias E, Anderson RN. How did cause of death contribute to racial differences in life expectancy in the United States in 2010? NCHS data brief, no 125. Hyattsville, MD: National Center for Health Statistics. 2013.  http://www.cdc.gov/nchs/data/databriefs/db125.pdf

2. Brooks X. Michael Douglas on Liberace, Cannes, cancer and cunnilingus. The Guardian. June 10, 2013.  http://www.guardian.co.uk/film/2013/jun/02/michael-douglas-liberace-cancer-cunnilingus

3. Herrero R, Castellsague X, Pawlita M et al. (2003) Human papillomavirus and oral cancer: the International Agency for Research on Cancer multicenter study. J Natl Cancer Inst. 2003;95(23):1772–1783.  http://jnci.oxfordjournals.org/content/95/23/1772

4. Markowitz LE, Hariri S, Lin C et al. Reduction in HPV prevalence among young women following HPV vaccine introduction in the United States, National Health and Nutrition Examination Surveys, 2003-2010. J Infect Dis. Advance online publication. doi: 10.1093/infdis/jit192. http://jid.oxfordjournals.org/content/early/2013/06/18/infdis.jit192

5. Cook NR, Lee I-M, Zhang SM et al. Alternate-Day, Low-Dose Aspirin and Cancer Risk: Long-Term Observational Follow-up of a Randomized Trial. Ann Intern Med. 2013;159(2):77-85.  http://annals.org/article.aspx?articleid=1709803

6. Pollack A. AMA recognizes obesity as a disease. New York Times. June 18, 2013.  http://www.nytimes.com/2013/06/19/business/ama-recognizes-obesity-as-a-disease.html

7. Reis JP, Loria CM, Lewis CE et al. Association Between Duration of Overall and Abdominal Obesity Beginning in Young Adulthood and Coronary Artery Calcification in Middle Age. JAMA. 2013;310(3):280-288.  http://jama.jamanetwork.com/article.aspx?articleid=1713590

8. O’Rourke RA, Brundage BH, Froelicher VF et al. American College of Cardiology/American Heart Association Expert Consensus Document on electron-beam computed tomography for the diagnosis and prognosis of coronary artery disease. J Am Coll Cardiol. 2000;36:326–340.  https://www.sciencedirect.com/science/article/pii/S0735109700008317

Primecuts – This Week In The Journals

July 15, 2013

By Matthew Light, MD

Faculty Peer Reviewed  

This week in the news and in the journals we look back at the Boston Strangler case, a previous pneumococcal vaccination strategy and we evaluate current coronary artery catheterization practices, and the risk of gastrointestinal bleeding related to the use of the new oral anticoagulants.

A break in the 50 year old Boston Strangler case links seminal fluid found at the crime scene of victim number eleven to long-suspected Massachusetts rapist, Albert DeSalvo [1]. DeSalvo was convicted of the string of “Green Man” rapes, landing him lifetime imprisonment. Only afterwards did he admit to the well-known murders, but was never formally tried due to a lack of evidence. Although he was found stabbed to death in a prison infirmary in 1973 making the matter legally moot, this evidence can now bring closure to the many people involved in the case.

Also in New England, The Journal that is, “U.S. Hospitalizations for Pneumonia after a Decade of Pneumococcal Vaccination” evaluates the efficacy of the seven-valent pneumococcal conjugate vaccine (PCV7) introduced in 2000 [2]. This vaccine has been shown to be effective in reducing vaccine-serotype pneumococcal disease in children and via the herd effect in adults. The authors asked whether this effect would persist especially with the concern for increasing disease caused by nonvaccine serotypes. Using the Nationwide Inpatient Sample database, expected rates of hospitalization for pneumonia (of which 20-60% are caused by pneumococcal disease) based on pre-vaccine data (1997-99) were compared to actual rates in the years following the vaccination program (2007-2009). With respect to adult data, patients between 65 and 74 had a decrease in annual rate of hospitalization of 85 cases per 100,000 population (HR 1.07), and those 75 to 84 had a decrease in rate of 360 per 100,000 (HR 1.15). Across all ages 168,000 fewer hospitalizations occurred than were expected based on 2007-2009 projections. This data supports that the early benefit seen in 2004 as a result of the vaccination program was not “eroded” by pneumococcal serotype replacement. A potential confounder is the addition of influenza vaccination to the childhood vaccination scheme in 2004, though the study reports that in 2007 only approximately 30% of children had received the vaccine. Now that PCV13, with coverage of 6 additional serotypes is available, this study serves to reiterate the public health implications of vaccinations for common pathogenic serotypes, an effect that appears to be robust despite colonization by non-vaccine serotypes.

Also on the subject of pulmonary infections, a review article in the New England Journal of Medicine discusses the clinical implications of bench research into inhibiting Influenza A replication [3]. The authors cite a study by Morita et al. which showed the omega three fatty acid derived protectin D1 (PD1) could inhibit influenza A replication in cell culture (RT-PCR data)[4]. Furthermore, mice infected with Influenza H1N1 and then treated with PD1 and peramivir showed statistically significant improvement in survival over those treated with peramavir alone (100% survival PD1 group vs 35% peramavir alone, p < 0.01). Though research into PD1 and other fatty acids potentially capable of inhibiting viral infection is new, authors of this review piece highlight an important concept: focusing on host characteristics, which change less frequently than the Influenza virus. By discovering and targeting natural host defenses, and specifically host “lipid factors”, we may be more successful in the treatment of influenza in the future.

In Cardiology news, researchers compared 222,000 patients in New York State and Ontario who underwent elective cardiac catheterization to determine whether the two fold increased rate of catheterization in New York is the result of an increased population burden of coronary disease or due to differences in patient selection for catheterization [5]. The study included patients older than 20 years of age without cardiac disease who underwent catheterization between 2008 and 2011. The main endpoint was observed rates of obstructive coronary disease, defined as left main stenosis greater than or equal to 50%, or stenosis of greater than or equal to 70% in major epicardial or branch vessels. Rates of obstructive coronary disease were significantly lower in New York State compared with Ontario (30.4% vs 44.8%, p < 0.001), as was the percentage of patients with left main or triple vessel disease (7% vs 13%, p < 0.001). After comparing models for predicting coronary disease across the two populations, researchers also found that only 19.3% of New York patients were predicted to have a 50% probability of obstructive disease prior to catheterization as compared to 41% of patients in Ontario (p < 0.001). An important conclusion was that these lower risk patients were more likely to undergo catheterization in New York State and that it is these patients who make up the majority of excess procedures, likely the result of physician preferences. In addition more asymptomatic patients underwent catheterization in New York, and fewer underwent non-invasive testing prior to catheterization. Though the study highlights a potential 75 million dollar savings if New York physicians were to adopt a similar rate of cardiac catheterization as those in Ontario, the decision to proceed to invasive testing is complex, factoring in both patient and provider characteristics which may not be immediately apparent from this study.

Finally, in the Gastroenterology literature is a meta-analysis looking at the rates of gastrointestinal bleeding (GIB) in patients exposed to new oral anticoagulants (nOACs) including thrombin and Xa inhibitors (specifically apixaban, rivaroxaban, and dabigatran) [6]. A total of 42 trials were included in the analysis (150,000 patients), including those looking at atrial fibrillation (8 studies), venous thromboembolism prevention following orthopedic surgery (21 studies), treatment of venous thromboembolism (6 studies), and acute coronary syndromes (5 studies). The study showed a modest but statistically significant increase in GIB for patients on nOACs compared with standard of care (OR 1.45, all p values significant and vary with statistical model).Much of this increased risk was attributed to the acute coronary syndrome trials (OR 5.21) in which the pooled number needed to harm was 24. This was likely the result of co-administration of antiplatelet agents. In subgroup analysis, dabigatran and rivaroxaban were the biggest offenders with OR of any GIB of 1.58 and 1.48 respectively, although direct comparison with apixaban has not been performed. Treatment of venous thrombosis was also associated with statistically significant increases in bleeding (OR 1.59). Though it is somewhat confusing to compare different nOACs, across different studies for different indications, a strength of this study is that it looks at bleeding risk from the perspective of the gastroenterologist, who must assess risk after these medications have already been started. Risk stratifying patients for bleeding is especially important as these anticoagulants have no known antidotes. Further investigation into GIB prophylaxis in patients on nOACs is also needed.

 Other notable reads for the week…

1. Lo-Coco F et al. Retinoic Acid and Arsenic Trioxide for Acute Promyelocytic Leukemia. N Engl J Med. 2013 Jul 11;369(2):111-21. doi 10.1056/NEJMoa130084. http://www.nejm.org/doi/full/10.1056/NEJMoa1300874

All-trans retinoic acid (ATRA) with anthracycline-based chemotherapy is currently the standard of care for acute promyelocytic leukemia. Given studies showing early efficacy and reduced hematologic toxicity of arsenic trioxide, this, in combination with ATRA, was compared with standard of care and showed non-inferiority, with complete remission in 100% of patients in the arsenic arm vs 95% in the standard of care arm. The regimen was associated with fewer infections but more hepatotoxicity.

2. Sawheny E et al. Iloprost Improves Gas Exchange in Patients with Pulmonary Hypertension and ARDS. Chest. 2013 Jan 31. doi 10.1378/chest. 12-2296. http://journal.publications.chestnet.org/article.aspx?articleid=1567238

Patients with acute respiratory distress syndrome (ARDS) can have elevated pulmonary artery pressures from several mechanisms including hypoxic vasoconstriction, acidosis, release of inflammatory cytokines, and thrombosis. This can result in worsening ventilation/perfusion mismatch and hypoxemia. Iloprost, a vasodilator approved for use in patients with pulmonary arterial hypertension, was given to 20 patients with ARDS and was found to improve PaO2 from a mean baseline of 82 mmHg to 100 mmHg (p < 0.01) without compromising respiratory mechanics or hemodynamics, highlighting it as a potential new tool in treatment of ARDS.

3. Hull, SC et al. Patient’s attitudes about the use of placebo treatments: telephone survey. BMJ 2013;346:f3757. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3698941/

An interesting look at the placebo effect without the use of deception…Greater than half the patients in this telephone survey felt that it was appropriate to prescribe a placebo treatment, with transparency and safety being top concerns.

Dr. Matthew Light is a 2nd year resident at NYU Langone Medical Center

Peer reviewed by Matthew Vorsanger, MD, associate editor, Clinical Correlations

Image courtesy of Wikimedia Commons

References:

1. 50 Years Later, a Break in a Boston Strangler Case. http://www.nytimes.com/2013/07/12/us/dna-evidence-identified-in-boston-strangler-case.html?hp&_r=0

2. Griffin MR et al. U.S. Hospitalizations for Pneumonia after a Decade of Pneumococcal Vaccination. N Engl J Med. 2013; 369:155-163. DOI: 10.1056/NEJMoa1209165. http://www.nejm.org/doi/full/10.1056/NEJMoa1209165

3. Baillie JK, Digard P. Influenza – Time to Target the Host? N Engl J Med 2013; 369:191-193. http://www.nejm.org.ezproxy.med.nyu.edu/doi/full/10.1056/NEJMcibr1304414?query=featured_home

4. Morita M et al. The Lipid Mediator Protectin D Inhibits Influenza Virus Replication and Improves Severe Influenza. Cell. 2013 Mar 28; 153(1): 112-125. http://www.cell.com/retrieve/pii/S009286741300216X

5. Ko DT et al. Prevalence and extent of obstructive coronary artery disease among patients under going elective coronary catheterization in new york state and ontario. JAMA. 2013 Jul 10;310(2): 163-9. doi: 10.1001/jama.2013.7834. http://jama.jamanetwork.com/article.aspx?articleid=1710454

6. Holster L et al. New Oral Anticoagulants Increase Risk for Gastrointestinal Bleeding: A Systematic Review and Meta-analysis. Gastroenterology. 2013;145:105-122. http://www.gastrojournal.org/article/S0016-5085(13)00290-4/abstract?referrer=http://www.ncbi.nlm.nih.gov/pubmed/23470618

Primecuts – This Week In The Journals

July 8, 2013

By Matthew Light, MD

Faculty Peer Reviewed

As summer continues, the heat presses on, the inevitable slow march towards shorter days progresses and NYU Langone Medical Center marked its first week with a new class of interns. There is much in the news including political unrest in Egypt, verbal escalation in the New York City mayoral race, and the release of new data in the fields of renal transplant and heart failure.

This week as America celebrated its independence, military forces removed democratically elected Egyptian president Mohamed Morsi on July 3rd. After nearly a year of public protest and in the face of a weakening Egyptian economy and supply shortages, Adli Mansour was installed as acting president of the interim government.[1]

With world leaders being ousted from their positions, we learn this week that so too can the failing transplanted kidney be removed, and potentially without the need for biopsy. A new prospective study from investigators at Weill Cornell Medical College and published in the New England Journal of Medicine evaluated urinary cell RNA levels in renal transplant patients in efforts to accurately diagnose rejection.[2] After testing a number of candidate RNAs, researchers found that a three gene model consisting of CD3e mRNA, IP-10 MRNA, and 18s rRNA boasted a 79% sensitivity,78% specificity and an area under the curve (AUC) of 0.85 for detecting acute rejection when compared to the gold standard of biopsy. This data certainly seems promising as levels of these three RNAs remain low in transplant patients with stable kidney function but increase predictably with acute cellular rejection, a treatable condition. The authors are hopeful that this assay may be used to monitor for signs of acute rejection without the need for biopsy. Thus, immunosuppressive therapy can be ramped up earlier, potentially avoiding irreversible graft damage and loss of the transplanted kidney.

In the financial world, European banking leadership supplied their own economic Fourth of July fireworks in the attempts to offset a withdrawal by the U.S. Federal Reserve from its money-printing program. Bank of England and European Central Banking officials simultaneously pledged allegiance to maintain or even lower interest rates for “an extended period of time”, sparking bottle rocket style explosions in major stock indexes worldwide.[3] As Americans celebrate the Fourth with beers, barbeque, and the inevitable elevation in our serum sodium, it’s hard not to wonder how many of those we could help if were able to preemptively halt congetive heart failure as suggested in the STOP-HF Randomized Trial published in JAMA.[4] Outpatients older than forty with either hypertension, hyperlipidemia, diabetes, obesity, vascular disease, arrhythmia or moderate/severe valvular disease were randomized to yearly BNP checks made available to their PMD vs. usual care. Patients in the intervention arm found to have BNP levels greater than 50 pg/mL were given mandatory referral to a specialized cardiovascular center along with an echocardiogram while those receiving conventional care were provided similar lifestyle modification counseling and referral to a cardiovascular specialist at the discretion of the patient’s physician. Patients in the intervention group received more Renin-Angiotensin-Aldosterone system (RAAS) based therapy, and had less LV dysfunction (5.3% intervention vs 8.7% control, p=0.003), and less emergency hospitalizations for cardiac events (22.3 events/1000 patient years intervention vs 40.4 control, p=0.002) compared with the control group. Though the optimal BNP cutoff for this type of risk stratification is debatable and likely varies with the patient population, the number needed to treat for this intervention to prevent a major CV adverse outcome requiring hospitalization was 48 over a one year period. This potentially places BNP screening in the same league as blood pressure control in terms of preventing cardiovascular events.

In local news and in true New Yorker style, mayoral candidate Anthony Weiner told a heckler who had been berating him for his stance on the Iraq War to “take a hike.” [5] Weiner definitively ended the dispute by pointing out that yelling was no way to converse and that he doesn’t “roll like that.” In keeping with this, a recent study in Chest from our very own Dr. Berger describes the phenotype of restrictive lung disease following World Trade Center dust exposure.[6] Study patients had physiology resembling a restrictive pattern which included a reduced vital capacity(VC) and total lung capacity (TLC), with preservation of the FEV1/FVC ratio. However, CT demonstrated no parenchymal abnormality, but instead bronchial wall thickening and air trapping. Furthermore, impulse oscillometry showed increased airway resistance with a small bronchodilator response. Predominant symptoms included cough and dyspnea, both present in 75% of patients. The data suggests a difference between classic restrictive physiology resulting from inspiratory dysfunction, and this new phenotype resulting from distal airway dysfunction.

Finally, since it is July, a piece in Annals “Once Upon a July (Saved)” is worth a look. In this piece an Internist looks back on her intern experience during her time on the Oncology ward.[7] Her first sick patient, a “liquid” referring to the patient’s hematologic malignancy, was crashing overnight. She felt alone, and terrified, until a veteran nurse came to the rescue giving calm and thoughtful advice. The author highlights two important points. First, how out of place she felt as an intern coming into a large academic program; a sentiment shared by many but rarely discussed. Second, in a mantra that should probably be repeated to physicians on a daily basis, “nurses are your friends.” and they are your colleagues and an invaluable resource both during training years, and beyond.

Also in the journals…

1. Margolis et al. Effects of home blood pressure telemonitoring and pharmacist management on blood control, a cluster randomized clinical trial. JAMA. 2013;310(1):46-56. doi:10.1001/jama.2013.6549.

Study participants (450 adults with uncontrolled hypertension treated in 16 clinics in the Minneapolis area) were randomized to home blood pressure monitoring with data transmission to their pharmacists (pharmacist could adjust medications) vs. standard PMD driven care. The intervention resulted in 27.2% more patients reaching their BP target compared with controls during the study period (12 months). Overall home blood pressure monitoring has advantages over physician and nurse practitioner in office BP checks including cost, convenience to the patient, and avoidance of white coat hypertension (to name a few). As long as this strategy does not overburden pharmacists it is a potentially effective means of managing hypertension in the outpatient setting.

2. Goldfine, AB et al. Salicylate in patients with type 2 diabetes: a randomized trial. Ann Intern Med. 2013;159(1):1-12. doi:10.7326/0003-4819-159-1-201307020-00003.

Patients randomized to salsalate 3.5 grams/day had an A1C level 0.37% lower than controls despite more reductions in diabetic medications over 48 weeks. The study was not held for long enough to determine whether the benfit of the intervension was sutainable..

Dr. Matthew Light is a 2nd year resident at NYU Langone Medical Center

Peer reviewed by Brian Greet, MD, Associate Editor, Clinical Correlations

Image courtesy of Wikimedia Commons

References:

[1] Army Ousts Egypt’s President; Morsi Is Taken Into Military Custody. http://www.nytimes.com/2013/07/04/world/middleeast/egypt.html?ref=todayspaper

[2] Suthanthiran, M et al. Urinary-cell mRNA profile and acute cellular rejection in kidney allografts. N Engl J Med. 2013;369:20-31.  http://www.nejm.org/doi/full/10.1056/NEJMoa1215555

[3] ECB, BoE easing signals send shares and bonds higher. http://www.reuters.com/article/2013/07/04/us-markets-global-idUSBRE88901C20130704

[4] Ledwidge, M et al. Natriuretic peptide-based screening and collaborative care for heart failure, the STOP-HF randomized trial. JAMA. 2013;310(1):66-74.

[5] Weiner to Heckler: ‘Take a Hike’. http://www.nytimes.com/2013/07/04/nyregion/weiner-to-heckler-take-a-hike.html?ref=todayspaper&_r=0

[6] Berger, K I. Lessons from the world trade center disaster: airway disease presenting as restrictive dysfunction. Chest. 2013; 144(1):249-257.  http://journal.publications.chestnet.org/article.aspx?articleid=1568885

[7] Nickas, G. Once upon a July (Saved). Ann Intern Med. 2013;159(1):68-69.

Primecuts – This Week In The Journals

July 1, 2013

By Matthew Vorsanger, MD and Brian Greet, MD

Faculty Peer Reviewed

Making health news this week, an ailing Nelson Mandela who has been hospitalized in an intensive care unit for over twenty days was visited by Barack Obama during his trip to South Africa. Considered a “personal hero”, President Obama was robbed of the ability to converse with the prior South African ruler due to the gravity of his illness. California, Nevada and parts of Arizona have been overwhelmed with near record triple digit temperatures resulting in over 170 people needing heat related treatment, as steps to protect the homeless and elderly are underway. Such events further put into perspective the recent morbidity and mortality weekly report from the CDC on June 7th which emphasized the need to protect vulnerable populations. [1] Senator Wendy Davis struggled to remain standing and on topic after ten hours of a planned thirteen hour filibuster hoping to block an abortion bill. Unable to lean on any objects for support, go the bathroom or eat, the efforts from the pink sneaker wearing senator from Texas were successful in aiding to prevent the new Texas abortion restrictions.

As we look back at all the events that transpired this past week, we also are looking ahead. The Look AHEAD research group prospectively randomized type 2 diabetics to intensive lifestyle interventions or to a control arm consisting of diabetic education with the aims to assess differences in cardiovascular outcomes. [2] While patients in the lifestyle intervention arm, which consisted of dietary modification through decreased caloric intake and increased physical activity, had significant reductions in weight and glycated hemoglobin, the results of their primary endpoint were disappointing. During a predefined interim analysis the study was prematurely discontinued after the review committee found, on the basis of a futility analysis, that both arms had similar rates of cardiovascular events despite their interventions.

While intensive lifestyle changes may not reduce the risk of cardiovascular endpoints in diabetics as we would have hoped, at least the combination of clopidogrel and aspirin may reduce the risk of those diabetics with minor strokes to have a subsequent larger cerebrovascular event. Conducted in China the CHANCE research group investigated the occurrence of stroke in patients who received aspirin and clopidogrel twenty four hours after a minor ischemic stroke or transient ischemic attack versus those who received placebo and aspirin. [3] Those randomized to receive aspirin and clopidogrel had an absolute risk reduction of 3.5% (8.2% versus 11.7%) compared to those receiving aspirin alone. Further reassuring outcomes revealed that the risk of hemorrhagic stroke was similar between the two groups (0.3% versus 0.3%) suggesting that dual antiplatelet therapy did not confer an additional bleeding risk.

What’s one of the first things that you do when a patient with acute heart failure is admitted to your service? Perhaps it’s ordering a low-sodium, fluid restricted diet. But is there any evidence to support this? As it turns out, previous studies, although underpowered, have not supported this. A new study this week in JAMA addressed this issue again by randomizing 75 patients admitted with acute decompensated systolic heart failure to a low-sodium, fluid restricted diet (800mg Na and 800cc fluid) versus an unrestricted diet [4]. Flying in the face of conventional wisdom, no differences in weight loss, hospital stay, or 30-day readmission rates were seen between groups. So think twice before you place that diet order!

Aanother study in this week’s issue of JAMA examined the utility of provocative cardiac testing in accelerated diagnostic protocols for coronary ischemia [5]. In 4181 patients who presented to emergency departments with chest pain, non-ischemic EKGs, and negative biomarkers, the utility of stress testing proved to be low. In fact, although 11.2% of patients had positive stress tests, 48.8% of these were false positives on coronary angiography. Only 28 patients overall had findings showing potential benefit from revascularization. In light of these results, a much less aggressive testing approach would likely be appropriate in patients with chest pain without evidence of any other high-risk features.

Other interesting reads this week…

1. Mahaffey KW, et al. Clinical outcomes with rivaroxaban in patients transitioned from vitamin k antagonist therapy: a subgroup analysis of a randomized trial. Ann Intern Med. 2013 Jun 18;158(12):861-8. doi: 10.7326/0003-4819-158-12-201306180-00003.  http://annals.org/article.aspx?articleid=1696643

With the advent of the new oral anticoagulants, questions have been raised not only about their safety in warfarin-naïve patients, but also in patients currently managed on warfarin. Although the ACTIVE W trial suggested a benefit to warfarin over other anticoagulant strategies, this subgroup analysis of the ROCKET-AF trial demonstrates similar safety and efficacy of rivaroxaban in warfarin-naïve vs experienced patients.

2. Stickrath C, et al. Attending rounds in the current era: what is and is not happening.

JAMA Intern Med. 2013 Jun 24;173(12):1084-9. doi: 10.1001/jamainternmed.2013.6041.  http://archinte.jamanetwork.com/article.aspx?articleid=1685887

Attending rounds on inpatient resident services are regarded as one of the cornerstones of house staff education. But what actually happens on them? A cross-sectional study of four teaching hospitals attempted to define this. Discussion of patient care was common (96.7% of the time), while discussion of evidence-based recommendations was rare (7.2%).

3. Guery B, et al. Clinical features and viral diagnosis of two cases of infection with Middle East Respiratory Syndrome coronavirus: a report of nosocomial transmission. Lancet. 2013 May 30. pii: S0140-6736(13)60982-4. doi: 10.1016/S0140-6736(13)60982-4. [Epub ahead of print]  http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2813%2960982-4/fulltext

More on the novel coronavirus that has been called “a threat to the entire world”. This case series describes two patients who presented with fever, chills, and myalgia progressing to respiratory failure requiring mechanical ventilation and extracorporeal membrane oxygenation.

Dr. Matthew Vorsanger is an Associate Editor, Clinical Correlations 

Dr. Brian Greet is an Associate Editor, Clinical Correlations

Peer reviewed by Neil Shapiro, MD, Editor-In-Chief, Clinical Correlations

Image courtesy of Wikimedia Commons

References:

[1] Heat-Related Deaths After an Extreme Heat Event — Four States, 2012, and United States, 1999–2009. Centers for Disease Control and Prevention. June 7, 2013. (Accessed June 29, 2013, at http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6222a1.htm

[2] The Look AHEAD Research Group. Cardiovascular Effects of Intensive Lifestyle Intervention in Type 2 Diabetes. N Engl J Med. 2013 Jun 24. [Epub ahead of print] PubMed PMID: 23796131.

[3] Wang Y, et al. Clopidogrel with Aspirin in Acute Minor Stroke or Transient Ischemic Attack. N Engl J Med. 2013 Jun 26. [Epub ahead of print] PubMed PMID: 23803136.

[4] Aliti GB, et al. Aggressive fluid and sodium restriction in acute decompensated heart failure: a randomized clinical trial. JAMA Intern Med. 2013 Jun 24;173(12):1058-64. doi: 10.1001/jamainternmed.2013.552. http://archinte.jamanetwork.com/article.aspx?articleid=1689981

[5] Hermann LK, et al. Yield of routine provocative cardiac testing among patients in an emergency department-based chest pain unit. JAMA Intern Med. 2013 Jun 24;173(12):1128-33. doi:  10.1001/jamainternmed.2013.850.  http://archinte.jamanetwork.com/article.aspx?articleid=1690009

Primecuts – This Week In The Journals

June 24, 2013

By Karin Katz, MD

Faculty Peer Reviewed

Last week, the U.S. Supreme Court unanimously ruled that human genes cannot be patented. The case involved Myriad Genetics, a company that patented the BRCA1 and BRCA2 genes in the late 1990s. Since then, the company has offered the most comprehensive test to detect gene mutations associated with breast and ovarian cancer risk, known as BRACAnalysis, with a price tag of over $3000. While the court ruled that “a naturally occurring segment” of DNA cannot be patented, complementary DNA can be. Political and scientific discussions on sharing genetic information have resumed as a result of this ruling, as well as new discussions on the implications for biotechnology and drug development. Now, let’s turn our attention to the realm of infectious disease where this week’s first journal, The Lancet, devotes their entire issue to HIV.

A randomized controlled trial by Choopanya et al. assessed whether antiretroviral pre-exposure prophylaxis in injection drug users in Thailand can reduce HIV transmission (1). Several previous trials have demonstrated a reduction in the risk of HIV infection with daily use of tenofovir-emtricitabine in certain high-risk populations (2,3). The recent Bangkok Tenofovir Study included 2400 men and women, ages 20-60 years, who were HIV-negative and reported injecting drugs during the previous year. Participants were randomly assigned to receive either daily tenofovir or placebo and were followed for a mean of 4 years. Most were men and the median age of participants was 31 years. The tenofovir and placebo groups reportedly had similar rates of injecting and sharing needles and similar numbers of sexual partners during follow up. Throughout the study, 50 participants became newly infected with HIV, which included 17 participants in the tenofovir group (an incidence of 0.35 per 100 person-years) compared to 33 in the placebo group (0.68 per 100 person-years). This represented a 48.9% relative risk reduction in HIV incidence in the intention-to-treat analysis (95% CI, 9.6–72.2, p=0.01). In earlier trials, prophylaxis with tenofovir-emtricitabine reduced the risk of HIV transmission by 44 to 75 percent in other high-risk populations, including men who have sex with men and sero-discordant heterosexuals (2,3). Taken together, these studies have provided data that led the CDC to publish interim guidelines (official guidelines due later this year) for prescribing pre-exposure prophylaxis in the groups at highest risk of HIV infection.

Another study published in the Lancet investigated a new therapeutic option for second-line antiretroviral therapy after first-line treatment failure for HIV (4). This non-inferiority trial was conducted at 37 sites worldwide in adults infected with HIV-1 with first-line treatment failure (defined as confirmed virological failure after 24 weeks or more). Virological failure was defined by two consecutive (at least 7 days apart) plasma HIV viral loads of more than 500 copies per mL. All patients received ritonavir-boosted lopinavir. Participants were then randomly assigned to receive a WHO-recommended regimen of 2 or 3 nucleoside or nucleotide reverse transcriptase inhibitors (control group), versus raltegravir, an integrase inhibitor. At 48 weeks, 81% of patients in the control group had a plasma viral load less than 200 copies per mL, compared to 83% of patients in the raltegravir group (difference of 1.8%, 95% CI, -4.7-8.3). The investigators concluded that the raltegravir regimen was non-inferior to the standard of care. The raltegravir regimen may offer some advantages for treating patients in whom first-line therapy has failed, compared to the current WHO-recommended regimen, including ease of administration. However, the high cost of raltegravir could limit the accessibility of this regimen to many parts of the world.

For more striking news in the world of infectious disease, the prevalence of HPV was reported to drop by half among vaccine-eligible girls (5). The vaccine was recommended as part of routine vaccination for females in 2006 and expanded to males in 2011. Among females aged 14-19 years, the vaccine-type HPV prevalence (6, 11, 16 or 18) decreased from 11.5% in 2003-2006 to 5.1% in 2007-2010. Of note, in 2007-2010 only 34% of females aged 14-19 years reported at least 1 HPV vaccine dose during that time period. The data was analyzed from the National Health and Nutrition Examination Surveys and included 8000 females aged 14 to 59 years. HPV prevalence was determined by assays of cervicovaginal samples; however, the data did not include Pap smear results. We do not know if the incidence of abnormal Pap results has changed since introduction of the vaccine. We do know that there has been a decrease in the incidence of genital warts among girls in this age group, which suggests early vaccine impact.

Moving on to rheumatology, a study in the New England Journal of Medicine investigated therapies for active rheumatoid arthritis after methotrexate failure (6). For patients who still have active disease despite therapy with methotrexate, many clinicians will add a TNF inhibitor (7). However, such biologic agents are extremely costly. The authors compared combined methotrexate with sulfasalazine and hydroxychloroquine (non-biologic DMARDS), to methotrexate with etanercept in patients with active disease. The primary outcome was the Disease Activity Score for 28-joint counts at 48 weeks. This scale includes the number of swollen and tender joints, the ESR, and patient-reported disease activity. All participants were treated with the dose of methotrexate they were on prior to starting the trial. In both groups, if patients did not have a response to the assigned therapy, they were switched to the other treatment group at 24 weeks. The results revealed that triple-therapy was noninferior to etanercept-methotrexate therapy, although there was more rapid clinical improvement in the etanercept-methotrexate group. This study suggests a cost-effective and safe approach to treating patients with active RA, although more studies are needed to compare the impact of these treatments on disease activity in the long term.

Also interesting this week:

1. Chlan et al. Effects of patient-directed music intervention on anxiety and sedative exposure in critically ill patients receiving mechanical ventilatory support: a randomized clinical trial. JAMA. 2013;309(22):2335-44. http://jama.jamanetwork.com/article.aspx?articleid=1687827

This study looked at the potential benefit of music therapy in awake ICU patients using patient-direct music, noise-cancelling headphone use, or standard care. Patient-directed music resulted in less anxiety than usual care, and in less sedation use.

2. Pan et al. Changes in red meat consumption and subsequent risk of type 2 diabetes mellitus: three cohorts of US men and women. JAMA Intern Med. 2013:1-8. Advance online publication. doi: 10.1001/jamainternmed.2013.6633. http://archinte.jamanetwork.com/article.aspx?articleid=1697785

As the summer heats up and we start to crave barbeque food, we sigh as we read the latest article with bad news about red meat. This study found that increasing red meat intake over a four-year period was associated with an elevated risk of T2DM. In addition, reducing red meat consumption by more than 0.50 serving per day from baseline was associated with a 14% lower risk of developing T2DM.

3. WHO: Interim guidance on the use of bedaquiline to treat MDR-TB. http://www.who.int/tb/challenges/mdr/bedaquiline/en/index.html

WHO issued “interim policy guidance” on the inclusion of bedaquiline, a new tuberculosis drug, in the combination therapy of multidrug resistant TB. Bedaquiline is the first FDA-approved TB drug in 40 years.

Dr. Karin Katz is an internal medicine resident at NYU Langone Medical Center

Peer reviewed by Matthew Vorsanger, MD, Associate Editor, Clinical Correlations

Image courtesy of Wikimedia Commons

References:

1. Choopanya, K et al. Antiretroviral prophylaxis for HIV infection in injecting drug users in Bangkok, Thailand (the Bangkok Tenofovir Study): a randomized, double-blind, placebo-controlled phase 3 trial. Lancet. 2013;381(983):2083-90. http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2813%2961127-7/fulltext

2. Grant RM et al. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med. 2010;363(27):2587.

3. Baeten JM et al. Antiretroviral prophylaxis for HIV prevention in heterosexual men and women. N Engl J Med. 2012;367(5):399.

4. Boyd, MA et al. Ritonavir-boosted lopinavir plus nucleoside or nucleotide reverse transcriptase inhibitors versus ritonavir-boosted lopinavir plus raltegravir for treatment of HIV-1 infection in adults with virological failure of a standard first-line ART regimen (SECOND-LINE): a randomised, open-label, non-inferiority study. Lancet 2013;381(9883):2091-9. http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2813%2961164-2/fulltext

5. Markowitz et al. Reduction in HPV prevalence among young women following HPV vaccine introduction in the United States, National Health and Nutrition Examination Surveys, 2003-2010. J Infect Dis. Advance online publication. doi: 10.1093/infdis/jit192. http://jid.oxfordjournals.org/content/early/2013/06/18/infdis.jit192

6. O’Dell JR, et al. Therapies for active rheumatoid arthritis after methotrexate failure. N Engl J Med. Advance online publication. doi: 10.1056/NEJMoa1303006. http://www.nejm.org/doi/full/10.1056/NEJMoa1303006

7. Update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis. Arthritis Care Res (Hoboken) 2012;64:625-639.

Primecuts – This Week In The Journals

June 17, 2013

By Brian Greet, MD

Faculty Peer Reviewed

Making headlines in the news this week 94 year old Nelson Mandela appears to be recovering after again being hospitalized for pneumonia. Thought possibly to be a complication of the tuberculosis he contracted while in prison, this is the second time the previous South African president has been hospitalized for pneumonia this year. The most destructive wildfire in Colorado history continues to wreak havoc, incinerating at least 450 homes. Controversy continues after Edward Snowden, a 29 year old a contractor for the National Security Agency, released information pertaining to the methods of surveillance of US citizens. Latest comments from Dick Cheney have posited the man as a “traitor” and “deeply suspicious obviously because he went to China.” Controversy has also surrounded the very public debate over angiotensin receptor blockers between two FDA officials. The debate between Thomas Marciniak and his boss Ellis Unger, has come from the link between ARBs and cancer risk. Marciniak contests that the safety of ARBs have been reliant on summary data from drug companies and despite early studies linking a potential increase in risk, not enough evaluation has not been performed to further evaluate the risk.

On the topic of ARBS, ACEs and RAAS inhibition, the ACC/AHA have released their 2013 guidelines for the management of heart failure this week [1]. Additions to this year’s guidelines include recommendations regarding the greater role of biomarkers and their guidance in clinically euvolemic outpatients, an approach to diagnosis of dilated cardiomyopathies with the use of genetics and family screening, an expanded indication for aldosterone blockade to now include NYHA class II, more clearly defined indications for cardiac resynchronization therapy, broader recommendations for the use of mechanical circulatory support in end stage heart failure, and much more.

Diabetes, a major contributor to systolic heart failure, is notoriously difficult to treat and can be frustrating for both provider and patient alike. Surgical options for potential cure have become an interesting area of intense research as of late. Evidence has shown bariatric surgery to be beneficial in improving glycemic control in those with a BMI of greater than 35, but it has remained unclear whether or not those with a lower BMI would benefit. In a systematic review in JAMA, Maggard-Gibbons et al looked at three randomized controlled trials looking at a total of 290 patients with BMIs between 30 and 35 undergoing bariatric surgery [2]. Surgery was associated with greater weight loss and improved glycemic control over the one to two years of follow up. While interesting in its findings, long term follow up still does not exist for this patient population and the morbidities of surgery may have been underestimated due to the selectivity in participating centers. Overall, it would be premature to recommend this treatment to those with a BMI between 30 and 35 but further research is certainly warranted.

With the summer months upon us, your friendly dermatologist is likely to recommend that you lather up with sunscreen. While previously based on expert recommendation from animal models, a new study from the Annals of Internal Medicine affirms such recommendations with its findings [3]. In this randomized controlled trial, 903 Australian patients younger than 55 years old were followed for an average of 4.5 years. In a two by two study design, half of patients were randomized to daily use of broad-spectrum “sun-protection factor 15+” sunscreen while the other half continued standard sun avoidance techniques. In addition, half of those assigned to the sun screen arm and half of those assigned to the control group were given 30mg of daily ?-carotene. Patients were followed with microtopography which was graded by assessors blinded to treatment allocation. While ?-carotene showed no overall effect on skin aging, those in the sunscreen group had 24% less skin aging. Although not a direct measurement of neoplasm, skin aging has been correlated to both actinic keratoses as well as skin cancer. These findings lend further credence to current common beliefs that sunscreen is beneficial and help to bolster common practice.

Continuing in the world of oncology, the results of a recent phase III trial entitled the DECISION trial were presented at the annual American Society of Clinical Oncology meeting in Chicago this week [4]. The trial investigated the use of sorafenib in locally advanced or metastatic patients with radioactive iodine-refractory differentiated thyroid cancer. Sorafenib, an oral inhibitor of VEGFR1-3 and Raf kinases, was randomly given to 207 of 417 patients included in the study. Patients all had locally advanced or metastatic RAI-refractory disease. The primary endpoint of investigation was progression-free survival. Median progression-free survival was found to be 10.8 months in the sorafenib arm versus 5.8 months in the placebo arm. Costs are estimated to be around $96,000 per year of treatment. This news is exciting given the lack of current therapeutic treatments for advanced thyroid cancer, though it still remains unclear whether or not this treatment will impact mortality.

Additional interesting reads this week…

Barefoot or Not?

Don’t lose the shoes just yet! The hallmark of barefoot running is that it promotes forefoot landing, whereas those wearing shoes are generally heel strikers. In this physiologic study, 37 experienced runners of whom 19 were habitual heel-strikers and 18 were fore-strikers were monitored for physiologic outcomes [5]. The participants were monitored using their natural method of running and then made to cross over into the opposite running style group where physiologic data was again recorded. Ultimately in this study heel-strikers won out in terms of running efficiency by a considerable margin requiring less oxygen consumption and burning fewer carbohydrates as a percentage of their energy exposure.

Dr. Brian Greet is Chief Medical Resident at NYU Langone Medical Center

Peer reviewed by Deborah Shapiro, MD, wife of Editor-In-Chief Neil Shapiro, Clinical Correlations

Image courtesy of Wikimedia Commons

References

[1] Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.J Am Coll Cardiol. 2013.  http://www.cardiosource.org/Science-And-Quality/Journal-Scan/2013/06/2013-ACCF-AHA-Guideline-for-the-Management-of-Heart-Failure.aspx

[2] Maggard-Gibbons M, Maglione M, Livhits M, et al. Bariatric Surgery for Weight Loss and Glycemic Control in Nonmorbidly Obese Adults With Diabetes: A Systematic Review. JAMA. 2013;309(21):2250-2261.  http://www.ncbi.nlm.nih.gov/m/pubmed/23736734/

[3] Maria Celia B. Hughes, Gail M. Williams, Peter Baker, Adèle C. Green. Sunscreen and Prevention of Skin Aging, A Randomized Trial. Annals of Internal Medicine. 2013 Jun;158(11):781-790.  https://annals.org/article.aspx?articleid=1691733

[4] Marcia S. Brose et al. (2013, May). Sorafenib in locally advanced or metastatic patients with radioactive iodine-refractory differentiated thyroid cancer: The phase III DECISION trial. 2013 ASCO Annual Meeting, Chicago, IL.

[5] Gruber AH, Umberger BR, Braun B, Hamill J. Economy and rate of carbohydrate oxidation during running with rearfoot and forefoot strike patterns. J Appl Physiol. 2013 May 16.  http://www.ncbi.nlm.nih.gov/pubmed/23681915