PrimeCuts

Primecuts – This Week In The Journals

February 18, 2014

By Miguel A. Saldivar, MD

Peer Reviewed

While walking through snowy streets of NYC, the sight of one or two innocent bystanders sliding on a patch of ice on the road is not uncommon. However, these unfortunate folks are far from being the only ones with a bruise or two: this week a widely accepted screening tool, the mammogram, received more than a few punches in the media.

The Cost of Mammography

The utility of mammography as a screening tool, questioned in a Canadian study published in the British Journal of Medicine (BMJ), is discussed in a separate article. [1,2]. This week, in the Annals of Internal Medicine, researchers gathered data from several patient surveys to assess (1) the costs of screening mammograms in the US in 2010 ($7.8 billion) and (2) to estimate how these costs would vary using different screening schedules. Guidelines by the American Cancer Society to screen women 40-84 yearly were compared with current European guidelines to screen women 50-69 biennially, and United States Preventive Services Task Force’s recommendation for risk-based screening in addition to biennial screening for women 50-74. The projected cost for mammographic screening using these guidelines were $10.1 billion/year, $2.6 billion/year and $3.5 billion/year respectively. The wide gap in these potential costs, in addition to recent studies questioning the utility of mammography as a screening tool [1, 2] raises concerns that current practices may be due for a change.

HPV Vaccines and Condyloma Incidence

In other women’s health news, the Journal of the American Medical Association (JAMA) published an observational cohort study to evaluate a possible dose-dependent effect of the HPV quadrivalent vaccine on the development of condyloma. [4] The study included females, ages 10-24 years in Sweden between 2006-2010, and aimed to assess an association between the number of doses of quadrivalent HPV vaccine (the full series consists of 3) and the incidence of condyloma.

The results were stratified based on age at first vaccination; comparisons were made between multiple different age groups, but the authors paid most attention to those aged 10-16 or 17-19 years. Results suggest a correlation between number of vaccination doses and Incidence Rate Reduction (IRR) for condyloma development. For individuals aged 10-16 at the time of the first vaccination, compared to those not vaccinated, after 1 dose IRR was 0.31 (95%, CI 0.20-0.49), IRR after 2 doses was 0.29 (95% CI, 0.21-0.40), and 3 doses was 0.18 (95% CI, 0.15-0.22). For women aged 17-19 after 3,2,and 1 doses the IRR was 0.23(95% CI, 0.18-0.29), 0.35 (95% CI, 0.26-0.47), and 0.35 (95% CI, 0.26-0.47) respectively. However, it should be noted that the overlap between the confidence intervals calls into question the paper’s conclusion that there is a true IRR difference based on number of doses. Further, the method of incidence collection (number of cases in the Patient Registry and number of prescriptions for podophyllotoxin and/or imiquimod) leaves out all patients who developed symptoms but did not seek medical attention and those who sought other treatments (e.g., cryotherapy, trichloroacetic acid, 5-fluorouracil/epinephrine gel).

With all of these flaws, one could argue that the relationship between number of doses and condyloma incidence will require further scrutiny before we can safely say that there is indeed a correlation between the number of vaccination dosages and condyloma development.

Viral Flu and Oseltamivir Use

Moving from women’s health to a topic affecting all genders, The Lancet Infectious Disease Journal published an article on the efficacy of oseltamivir to reduce illness duration and viral shedding in people with influenza when started within 5-days of symptom onset [5]. This double-blind, randomized, placebo-controlled trial done in urban Bangladesh compared patients with confirmed Influenza who started treatment with Oseltamivir less than 48 hours after symptom onset to those who initiated treatment later. The primary endpoints were duration of clinical illness and viral shedding. Influenza positivity was determined by nasal washings tested with a rapid diagnostic test (QuickVue, Quidel) for Influenza A or B. Patients were then followed for duration of symptoms after initiation of oseltamivir. Viral shedding was qualified by PCR detection, virus isolation and virus titer at days 2, 4 and 7.

In the group that began treatment less than 48 hours after symptom onset, the median duration of symptoms was 3 days for oseltamivir and 4 days for placebo (p=0.01). In the group beginning treatment greater than 48 hours after symptom onset, median duration of symptoms was 3 days with both the oseltamivir and placebo groups (p=0.04). While these results are not particularly impressive, oseltamivir did significantly reduce virus isolation on day 2 (ARR 10%, NNT 10), day 4 (Absolute Risk Reduction 7%, NNT 14) and day 7 (ARR 6%, NNT 17). These results raise the question of oseltamivir’s clinical utility in controlling spread of the disease rather than individual symptom/disease management.

Sentinal Node Biopsy vs Observation in Melanoma

In oncologic news, the New England Journal of Medicine published the final report of a study comparing outcomes of sentinel node biopsy vs nodal observation in primary cutaneous melanoma [6]. In this trial patients were randomized to wide excision plus nodal observation and lymphadenectomy for recurrence (observation group) or wide excision plus sentinel-node biopsy and immediate lymphadenectomy if metastasis was detected (biopsy group). Ten-year disease-free survival rates were stratified by melanoma thickness. In patients with intermediate thickness melanomas (1.2-3.5mm deep), 10-year disease-free survival was 71.3% vs 64.7% (biopsy vs observation), with corresponding ARR of 6.6%. Among patients with thick melanomas (>3.5mm), 10-year disease-free survival was 50.7% vs 40.5% (biopsy vs observation), with corresponding ARR of 10.2%. Although current recommendations for management of melanoma include elective complete lymphadenectomy regardless of nodal metastasis, this new data suggests an increased rate of disease-free survival in patients undergoing less aggressive surgical diagnostic treatment. Sentinel node biopsy is a minimally invasive procedure that carries with it a lesser risk of morbidity than complete lymphadenectomy, potentially contributing to reduced morbidity and mortality.

This weeks’ news cycle consisted largely of new data questioning the utility and efficacy of already available diagnostic modalities and, perhaps suggesting that aggressive prevention and treatment does not always improve outcomes. Just as uncertain as the next snowfall, we cannot predict future policies or treatments. However, we can use the new data available to question, and subsequently improve, current practices.

ALSO IN THE NEWS

Other articles circulating in this week’s medical journals include:

* A position paper from the American College of Physicians describing the public health issue of prescription drug abuse. With deaths from drug overdose now becoming the 2nd leading cause of death from unintentional injuries in the U.S. (second only to motor vehicle collisions) this position paper seeks to provide guidance on ways to address this growing problem. [7]

* CVS Pharmacies is planning to stop selling tobacco products. An announcement of this nature coming from a major corporation now makes international news in the medical literature with articles in both the BMJ and JAMA. [8, 9]

* The Annals of Internal Medicine published a restrospective analysis of repeated endoscopy in the Medicare population. Researchers found that nearly one half of repeat EGD’s were performed in patients who already had a diagnosis, or who had previous findings that failed to suggest the need for repeat examination, bringing into question overuse of endoscopy in this population. [10]

* The Journal Chemical Science published a report on Surface-enhanced Raman Spectroscopy as a new method to detect and simultaneously quantify pathogens in bacterial meningitis. This could significantly reduce waiting time as compared to standard CSF cultures and thus allow for faster delivery of targeted treatments. [11]

Dr. Miguel A. Saldivar is a 1st year resident at NYU Langone Medical Center

Peer reviewed by Jessica Taff, MD, 3rd year resident at NYU Langone Medical Center

Image courtesy of Wikimedia Commons

References:

1. Twenty five year follow-up for breast cancer incidence and mortality of the Canadian National Breast Screening Study: randomised screening trial. Miller, et al. BMJ 2014;348:g366 doi: 10.1136/bmj.g366. http://www.bmj.com/content/348/bmj.g366

2. Mammograms in the News, Yet Again. Miguel A Saldivar, MD. Clinical Correlations, the NYU Langone Online Journal of Medicine. February 13, 2014. https://www.clinicalcorrelations.org/?p=7352

3. Aggregate Cost of Mammography Screening in the United States: Comparison of Current Practice and Advocated Guidelines. O’Donoghue, et al. Ann Intern Med. 2014;160(3):145-153-153. doi:10.7326/M13-1217. http://annals.org.ezproxy.med.nyu.edu/article.aspx?articleid=1819118

4. Association of Varying Number of Doses of Quadrivalent Human Papillomavirus Vaccine With Incidence of Condyloma. Herweijer, et al.  JAMA. 2014;311(6):597-603. doi:10.1001/jama.2014.95. http://jama.jamanetwork.com.ezproxy.med.nyu.edu/article.aspx?articleid=1829685

5. Efficacy of oseltamivir treatment started within 5 days of symptom onset to reduce influenza illness duration and virus shedding in an urban setting in Bangladesh: a randomised placebo-controlled trial. Fry, et al. The Lancet Infectious Diseases, Volume 14, Issue 2, Pages 109 – 118, February 2014. doi:10.1016/S1473-3099(13)70267-6. http://www.thelancet.com/journals/laninf/article/PIIS1473-3099%2813%2970267-6/fulltext

6. Final Trial Report of Sentinel-Node Biopsy versus Nodal Observation in Melanoma. Morton, et al. N Engl J Med 2014; 370:599-609February 13, 2014. DOI: 10.1056/NEJMoa1310460. http://www.nejm.org.ezproxy.med.nyu.edu/doi/full/10.1056/NEJMoa1310460?query=featured_home

7. Prescription Drug Abuse: Executive Summary of a Policy Position Paper From the American College of Physicians. Kirschner, et al. Ann Intern Med. 2014;160(3):198-200-200. doi:10.7326/M13-2209. http://annals.org.ezproxy.med.nyu.edu/article.aspx?articleid=1788221

8. Major US pharmacy chain plans to stop selling cigarettes. McCarthy, Michael. BMJ 2014;348:g1442. http://www.bmj.com.ezproxy.med.nyu.edu/content/348/bmj.g1442

9. Ending Sales of Tobacco Products in Pharmacies. Brennan, et al.  JAMA. Published online February 05, 2014. doi:10.1001/jama.2014.686. http://jama.jamanetwork.com.ezproxy.med.nyu.edu/article.aspx?articleid=1828530

10. Repeated Upper Endoscopy in the Medicare Population: A Retrospective Analysis. Pohl, et al. Ann Intern Med. 2014;160(3):154-160-160. doi:10.7326/M13-0046. http://annals.org.ezproxy.med.nyu.edu/article.aspx?articleid=1819119

11. Simultaneous detection and quantification of three bacterial meningitis pathogens by SERS. Gracie, et al. Chem. Sci., 2014,5, 1030-1040. DOI: 10.1039/C3SC52875H. http://pubs.rsc.org/en/content/articlelanding/2014/sc/c3sc52875h#!divAbstract

 

 

 

 

Primecuts – This Week In The Journals

February 10, 2014

By Luke O’Donnell, MD

Peer Reviewed

I guess being single in New York should make me dread Valentine’s Day. But I don’t. Maybe it is my years of studying a language that has words to distinguish love in all its manifestations: the once-in-a-lifetime stuff (amour) versus the form with the same amount of intimacy but less commitment (amant). Anyway, enjoy the first article; it is about an emerging communicable disease. Kisses everyone.

If the ever-looming scare of H5N1 was not enough, the New England Journal of Medicine (NEJM) published an epidemiological study concerning a novel avian influenza (H7N9) that is emerging in eastern China. Following the international scare of severe acute respiratory syndrome (SARS), the Chinese government instituted national surveillance of pneumonia of unknown origin. In February 2013, the database showed an increase in rapidly progressing severe pneumonia. H7N9 was later found to be the cause. There were 139 confirmed cases between February and December 2013, which by the researcher’s models correlates with 27,000 (95% CI, 9350-65000) symptomatic cases [1].

Of these patients, most were older (interquartile range 46-73 years), men (71%), urban dwellers (73%), who had some unspecified underlying medical condition (73%), with a history of animal exposure (82%). Interestingly only 9% of these confirmed cases were in poultry workers. The vast majority of patients were exposed to livestock at urban animal markets where chickens were the primary culprit in 82% of cases [1].

In affected patients, the disease course proved to be severe. The incubation period lasted an average of 6 days, after which symptoms became so overwhelming that 99% of patient needed hospitalization. Ninety percent of these patients were deemed to have pneumonia in lower respiratory track or respiratory failure. Sixty-three percent of patients required intensive care unit (ICU) monitoring. Of the confirmed cases, there was a 34% case fatality, usually from acute respiratory distress syndrome (ARDS) or multi-organ failure [1].

More concerning was the possible human-to-human viral spread in four identified “family clusters.” Studies of these families showed likely spread from the index patient who usually had some history of livestock exposure to a family member who had no contact with animals in any way. While these secondary patients usually had very close/intimate contact with the index patient, there is a fear that viral mutations could make human-to-human transmission easier [1].

While the researchers noted that cases petered out after May 2013, an editor’s note states that there has been an additional 60 confirmed cases since the end of the study period (December 1, 2013). This resurgence possibly correlates with the northern flu season [1].

And if you are inclined to chuck dizziness with the likes of “total body pain,” the Mayo Clinic publish a study that makes this otherwise eye-rolling complaint a whole lot scarier.

Harvard researchers investigated the relationship between dizziness and acute stroke in non-straight forward cases. Citing a 1989 Annual of Emergency Medicine article in this study, dizziness (in all its descriptive nuances that included vertigo, lightheadedness, gait instability) is secondary to a serious cause in 30% of cases. Strokes in the posterior fossa are particularly associated with this complaint and dizziness can be the sole presenting symptom in 10% of cases [2].

In this study, researchers imaged all patients with self-reported complaints of dizziness with unclear etiology. Patients with a straightforward reason for their dizziness were excluded, such as those with focal neurological deficit (clear evidence of a stroke), acute ST-segment elevation, active hemorrhage, hypotension, orthostatic vital signs, diarrheal illness, and hypoglycemia among others. The remaining patients were then imaged either by computer tomography (CT) or magnetic resonance imaging (MRI) and read by the neurology department [2].

Of the 473 patients imaged, 14 (3%) were found to have acute stroke. Unsurprising, these 14 patients were more likely to be older,have hyperlipidemia, hypertension, and coronary artery disease. Interestingly, abnormal tandem gait test was associated with stroke (OR, 3.13; 95% Cl, 1.10-8.89). The rest of the physical exam did not hold up as well: nystagmus, Dix-Hallpike, dysmetria, ataxia, Romberg all had no association with or against acute stroke. In this study, ED clinicians—attendings and emergency medicine residents—were also told to judge the likelihood of stroke as low, moderate, high in these patients before seeing any imaging. As painful as it might be to hear, their gestalt proved the best predictor of strokes in this study (OR, 18.8; 95% CI 4.17-74.5) [2]. This study reflects the benefits of clinical judgment and the ability to synthesize the different aspects of the patient’s history and presentation, over just sole isolated findings.

This next article is for those who share a bed. If they don’t snore now, they probably will…and you have options.

Obstructive sleep apnea (OSA) causes considerable health risks: excessive sleepiness, insulin resistance, vascular disease, and increased risk of death among others. Continuous positive airway pressure is the usual go-to treatment option, but has low patient compliance. A newer possible therapy is hypoglossal nerve stimulation (HGNS). The onset of apnea is accompanied by reduced stimulation of the upper airway muscles leading to decreased patency. With HGNS, an implanted electrode simulates the hypoglossal nerve causing genioglossus contraction and tongue protrusion leading to upper airway patency. This device works by placing a pulsatile electrode on the hypoglossal nerve. The electrode is linked with a ventilator sensory device that is embedded in the fourth intercostal region. Patients activate the device before going to bed. While sleeping, the hypoglossal nerve is stimulated to open up the airway with inspiration [3].

In a NEJM-published prospective cohort study, 126 patients with moderate-to-severe obstructive sleep apnea with poor CPAP compliance were implanted with the device. Patients were then followed for level of sleepiness, apnea-hypopnea index (AHI), and the oxygen desaturation index (ODI). AHI is the number of apnea or hypopnea events per hour. ODI is the number of times per hour that saturation drops more than 4 percentage points below baseline. Patients were followed with polysomnographic study before device activation then at 2, 6, 12 months afterwards. Sleepiness was judged on the Epworth scale and the Functional Outcomes of Sleep Questionnaire (FOSQ) [3].

Results were promising. At 12 months, the AHI decreased by 68%, from 29.3 pre-intervention to 9.0 post intervention. ODI score decreased by 70%, from 25.4 to 7.4. Symptoms of sleepiness also significantly improved. FOSQ increased by 2.9 points (95% CI 2.4-3.5), which was greater than the usually 2-point increase typically consistent with clinical meaningful improvement. The Epworth Sleepiness Scale score at 12 months was consistent with normalization—meaning the score was less than 10, which is consistent with the general public [3].

To further verify these results, researchers blindly withdraw therapy in 46 patients. After 1 week, the mean AHI increased from 7.6 to 25.8 (P<0.001) [3].

So basically if your amour/amant snores (no judgment), there might be other options besides sleeping next to Darth Vader.

Other studies circulating in this week’s literature include:

1. In a retrospective study, active tuberculosis (TB) was found to be an independent risk factor for venous thromboembolism. Using ICD-9-CM codes, researchers searched a database of 30 million for patient with codes for both TB and pulmonary embolism (PE) and/or deep vein thrombosis (DVT). Active TB was found to confer a greater risk of VTE compared to those without TB (odds ratio, 1.55 [95% CI, 1.23-1.97]) [4].

2. In a study in mice, neutralization of IL-1 and IL-18 with anakinra (a IL-1 receptor antagonist) and anti-IL-10 antibodies conferred complete protection from endotoxin-induced lethality associated with sepsis. The importance of this study is that previous focus was on the upstream activators CAPS1 and CAPS11 [5].

3. The Xpert MTB/RIF assay is an automatic nucleic-acid amplification test that can detect both mycobacterium tuberculosis (MTB) complex DNA and rifampicin (RIF) resistance in 2 hours. The targeted audience is developing countries where it could aid with both TB and resistance pattern diagnosis in the primary care setting. The Lancet published a study showing that Xpert MXRT/RIF could be administered successfully by nurses leading to decreased time to treatment commencement. However TB-related morbidity did not decrease. Researchers felt that it was likely secondary to high-levels of empiric treatment in smear-negative or smear-pending patients [6].

4. Young and middle-aged patients with fibromyalgia have poorer quality of life and worst symptoms than older patient with this diagnosis. These patients were also found to have both reduced mental and physical health compared to women of their same age group who did not have fibromyalgia [7].

Coming out this V-day is a less-than-Oscar-worthy movie about nurses in Manhattan…their schedules are just murder (and I stole that line). If you are otherwise too occupied to catch this slasher film Friday night, I posted the trailer here your convenience: http://www.youtube.com/watch?v=nEtzKmfDTU4

Dr. Luke O’Donnell is a 1st year resident at NYU Langone Medical Center

Peer reviewed by Arnab Ghosh, MD, Contributing Editor, Clinical Correlations

Image courtesy of Wikimedia Commons.

References:

1, Li Q, Zhou L, Zhou M et al. Epidemiology of Human Infectious with Avian Influenza A(H7N9) Virus in China. New England Journal of Medicine. 370(6), 520-532, 2014. http://www.nejm.org/doi/full/10.1056/NEJMoa1304617

2, Chase M, Goldstein JN, Selim MH et al. A Prospective Pilot Study of Predictors of Acute Stroke in Emergency Department Patients With Dizziness. The Mayo Clinic Proceedings. 89(2), 173-180. 2014. https://www-clinicalkey-com.ezproxy.med.nyu.edu/#!/ContentPlayerCtrl/doPlayContent/1-s2.0-S0025619613009786

3, Strollo PJ, Soose RJ, Maurer JT et al. Upper-Airway Stimulation for Obstructive Sleep Apnea. The New England Journal of Medicine. 370(2). 139-148. 2014. http://www.nejm.org.ezproxy.med.nyu.edu/doi/full/10.1056/NEJMoa1308659

4, Dentan C, Epaulard O, Saynaeve D et al. Active Tuberculosis and Venous Thromboembolism: Association According to International Classification of Diseases, Ninth Revision Hospital Discharge Diagnosis Codes. Clinical Infectious Diseases 58(4), 495-501. 2014. http://cid.oxfordjournals.org.ezproxy.med.nyu.edu/content/58/4/495

5, Van Den Berghe A, Demon D, Bogart P et al. Simultaneous Targeting of IL-1 and IL-18 is Required for Protection against Inflammatory and Septic Shock. American Journal of Respiratory and Critical Care Medicine 189(3), 282-291. 2014. http://www.atsjournals.org.ezproxy.med.nyu.edu/doi/abs/10.1164/rccm.201308-1535OC?journalCode=ajrccm#.UvQ9o_1CflI

6, Theron G, Zijenah L, Chanda D et al. Feasibility, accuracy, and clinical effect of point-of-care Xpert MTB/RIF testing for tuberculosis in primary-care settings in Africa: a multicenter, randomized, controlled trail. The Lancet. 383, 424-435. 2014. http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(13)62073-5/fulltext

7, Jiao J, Vincent A, Cha SS et al. Relation of Age With Symptom Severity and Quality of Life in Patients with Fibromyalgia. The Mayo Clinic Proceedings. 89(2), 199-206. 2014. https://www-clinicalkey-com.ezproxy.med.nyu.edu/#!/ContentPlayerCtrl/doPlayContent/1-s2.0-S0025619613009816

 

 

Primecuts – This Week In The Journals

February 3, 2014

By Elizabeth Park, MD

Peer reviewed

Super Bowl fever also hit Times Square this week as tens of thousands of people headed to the New York metropolitan area for the Super Bowl. The Super Bowl is more than just a football game. Like Thanksgiving, it’s the day for friends and family to get together, sit down in front of TV with accompanying chips, pizza, chicken wings and beer. You can easily consume 2000 calories during the game, interrupting your New Year’s diet plan.

Speaking of diet, recently there has been a randomized trial that supports dietary intervention in decreasing the risk of atherosclerotic diseases, including peripheral artery disease (PAD). Traditional recommendations for PAD reduction include smoking cessation, low fat and low salt diet, optimal management of chronic disease including hypertension and diabetes. Ruiz-Canela et al. published an analysis of a randomized trial, PREDIMED, a multicenter, randomized, blinded, primary prevention dietary trial conducted in Spain between 2003-2010, with a total of 7447 participants. Its primary end point was a composite of myocardial infarction, stroke, and death. Participants were men and women without clinical PAD or baseline cardiovascular disease but with diabetes or at least 3 cardiovascular risk factors. They were randomized to 1 of 3 groups: a Mediterranean diet supplemented with extra-virgin olive oil; a Mediterranean diet supplemented with nuts or; counseling on a low-fat diet (control group). Both Mediterranean diet interventions were associated with a lower risk of PAD compared to the control group with HR 0.34 (95% CI, 0.2-0.58) for the extra-virgin olive oil group and HR 0.50 (95% CI, 0.30-0.81) for the nuts group compared with the control group, adjusted for classic atherosclerotic risk factors. The number needed to treat to prevent 1 PAD case per year was 336 (95% CI, 269-566) and 448 (95% CI, 316-1536) for the Mediterranean diet supplemented with extra-virgin olive oil and the Mediterranean diet plus nuts group respectively. This was the first randomized primary prevention trial supporting previous observational studies in support of dietary interventions to decrease the  risk of PAD. However, given the number needed to treat is quite high to prevent 1 clinically symptomatic case per year, it may be hard to apply to clinical practice despite its benefit [1].

After explaining to your patients what exactly a Mediterranean diet is, you could also increase their awareness of childhood obesity by discussing its rising prevalence. Children with body mass index (BMI) at or above 95th percentile among children (age 6-11) increased from 4.2% in 1963-1965 to 15.3% in 1999-2000. Cunningham et al. examined the incidence of childhood obesity in an attempt to better understand its epidemiology. Researchers evaluated data from a large longitudinal study of children (the Early Childhood Longitudinal Study, Kindergarten Class of 1998-1999) to obtain a representative prospective cohort of 7738 participants who were then followed over 10 years between 1998 and 2007. The prevalence of obesity was defined as the proportion of all children in each age group who were obese. The incidence was defined as the occurrence of a new case of obesity in a child who was not previously obese. Data interpretation showed the prevalence of obesity increased with age, reaching 20.8% by eighth grade (mean age 14.1 years), while the incidence of obesity was highest at the youngest ages (5.4% among kindergartners) and declined through eighth grade. The incidence of obesity was 4 times as high among children who had been overweight at the age of 5 years compared to those with a normal weight at that age (RR 4.04, 95% CI, 3.29-4.96). The authors suggest that the course of obesity may be already established at very young age [2].

Would you like to know what’s new in oncology? Researchers have found that there might be a new therapeutic target in human colorectal cancer. Past research has shown enrichment of cancer-initiating cells (CICs, with the key property unique to CICs being self-renewal) in tumors that survive therapy poses a challenge in the treatment of cancer. A study by Kreso et al. specifically looked at human colorectal CIC function. They found that CIC function is dependent on the regulator BMI-1 which is strongly linked to self-renewal and maintenance of stem cells. The treatment of primary colorectal cancer xenografts with small molecule-mediated BMI-1 inhibition (via a compound called PTC-209) resulted in impairment of tumor growth. These findings may potentially be used to develop new therapeutic treatment of colorectal cancer by inhibiting self-renewal ability of CICs [3].

Is magnetic resonance enterography (MRE) a reliable tool to monitor therapy in patients with Crohn’s? A recent article from Gastroenterology can help you answer this question. The study done by Ordas et al. was a prospective multicenter study of 48 patients with active Crohn’s, examining patients who underwent ileocolonoscopy and MRE at baseline and 12 weeks after treatment with steroid or tumor necrosis factor inhibitor (specifically adalimumab). The primary end points for the study were determining the accuracy of MRE in identifying ulcer healing (defined as the disappearance of ulcers on endoscopic exam) and the endoscopic remission (quantified using Crohn’s Disease Endoscopic Index of Severity <3.5). MRE identified ulcer healing with 90% accuracy (area under the curve [AUC] 0.83, 95% CI, 0.713-0.953, P<0.001) and endoscopic remission with 83% accuracy (AUC 0.864, 95% CI, 0.75-0.987, P<0.001), supporting the reliability of MRE as a tool in assessing response to treatment in patient with Crohn’s [4].

Also in the literature this week:

1. In postmenopausal women with low bone mineral density, romosozumab (a monoclonal antibody binding to sclerostin—an soteocyte-derived inhibitor of osteoblast activity) was associated with significant increased bone density and decreased bone resorption at 12 months [5].

2. A systematic review from the British Medical Journal suggests that patients with acute myocardial infarction (MI) presenting during off-hours (weekends and nights) have higher mortality and patients with ST-elevation MI have longer door to balloon times, voicing the need for efforts to improve systems of care, regardless of time of the day or day of the week [6].

3. Can antioxidants be harmful? Recent research published in Science suggests that exogenous antioxidants (via supplementing the diet with N-acetylcysteine [NAC] and vitamin E) accelerated lung cancer progression in mice. RNA sequencing showed the above antioxidants reduced expression of endogenous antioxidant genes, thereby producing changes in tumor transcriptome profiles. Researchers raise concern that antioxidants may accelerate the growth of early tumors or precancerous lesions in high risk populations including smokers and COPD patients using NAC [7].

4. Neck pain is a common condition affecting about 4.9% population, ranked 4th highest in terms of disability (measured by years lived with disability) and 21st in terms of overall burden (estimated as disability adjusted life years) from the Global Burden of Disease 2010 study [8].

Dr. Elizabeth Park is a 2nd year resident at NYU Langone Medical Center

Peer reviewed by Arnab Ghosh, MD, Contributing Editor, Clinical Correlations

Image courtesy of Google Images

References

1. Ruiz-Canela M, Estruch R, Corella D et al. Association of Mediterranean Diet With Peripheral Artery Disease: The PREDIMED Randomized Trial. JAMA. 2014; 311(4):415-417.  http://jama.jamanetwork.com/article.aspx?articleid=1817779

2. Cunningham SA, Kramer MR, Venkat Narayan KM et al. Incidence of Childhood Obesity in the United States. N Engl J Med. 2014; 370:403-411.  http://www.nejm.org/doi/full/10.1056/NEJMoa1309753

3. Kreso A, Galen P, Pedley N et al. Self-renewal as a Therapeutic Target in Human Colorectal Cancer, Nature Medicine. 2014; 20:29-36.  http://www.nature.com/nm/journal/v20/n1/full/nm.3418.html

4. Ordas I, Rimola J, Rodriguez S et al. Accuracy of Magnetic Resonance Enterography in Assessing Response to Therapy and Mucosal Healing in Patients With Crohn’s Disease. Gastroenterology. 2014; 146: 374-382.  http://www.gastrojournal.org/article/S0016-5085(13)01561-8

5. Michael R. McClung MR, Grauer A, Boonen S et al. Romosozumab in Postmenopausal Women with Low Bone Mineral Density. N Engl J Med 2014; 370:412-420.  http://www.nejm.org/doi/full/10.1056/NEJMoa1305224

6. Sorita A ,Ahmed A ,Starr SR et al. Off-hour presentation and outcomes in patients with acute myocardial infarction: systematic review and meta-analysis. BMJ 2014;348:f7393  http://dx.doi.org/10.1136/bmj.f7393

7. Savin VI, Ibrahim MX, Larsson E et al. Antioxidants Accelerate Lung Cancer Progression in Mice. Sci Transl Med. 2014;29(6):221ra15  http://stm.sciencemag.org/content/6/221/221ra15

8. Hoy D, March L, Woolf A et al. Clinical and epidemiological research: Extended report: The global burden of neck pain: estimates from the Global Burden of Disease 2010 study. Ann Rheum Dis annrheumdis-2013-204431Published Online First: 30 January 2014  http://dx.doi.org/10.1136/annrheumdis-2013-204431

 

 

Primecuts – This Week In The Journals

January 27, 2014

By Luke O’Donnell, MD

Peer Reviewed

This was a week of confusion both old and new. How did a chance of flurries become a major winter storm? Did Beyoncé sign “Happy Birthday” to first lady Obama? What strain of cholera caused the 1849 Philadelphia Pandemic?

This week’s medical literature may not have cleared up all these pressing questions, but at least it managed to determine the strain of Vibrio cholerae that caused the devastating Philadelphia cholera outbreak of 1849. Vibrio cholerae’s predominate pathogenic strain—serogroup O1—has two genetically different biostrains: classic and El Tor. For unknown reasons in the 20th century, El Tor replaced classic as the predominate pathogenic biotype. This week the New England Journal of Medicine (NEJM) report helped confirm the timeline of this transition and investigate its possible reasons. From the 150 year-old preserved intestines of a pandemic victim, Vibrio cholerae DNA was extracted, sequenced, and compared to current day classic genotype O395. The DNA from the 1849 pandemic had 95-97% similarity to classical O395 Vibrio cholerae genome, helping demonstrate that the classic biostrain was the predominate pathogen during this period. Genome comparisons also provided possible reasons for the change in the predominant cholera pathogen. The cholera sample from the 1849 victim had longer tandem arrays of cholera toxin phage (CTX) than current-day O395 classic Vibrio cholerae. CTX is the main virulent factor. These tandems suggest possibly increased virulence, but the actual functional implications remain unclear—these repeats could possibly be uncoded and without actual pathologic significance [1].

And if you were worried that this confusion was just secondary to early dementia, well…you should probably continue to be really worried. Two studies published this week in the NEJM investigating monoclonal antibody therapies as treatments for Alzheimer’s disease failed to show benefit. Both studies involved targeting amyloid-beta as a means to reduce plaque formation with hopes of at least sustained mental status in patient’s with mild-to-moderate Alzheimer’s disease.

The first study investigated solanezumab, a humanized monoclonal antibody that binds to soluble amyloid-beta, with two double-blind trails (EXPEDITION 1 and EXPEDITION 2) involving about 2,000 patients in all. Four hundred milligrams of solanezumab was infused every 4 weeks for 18 months. Clinical outcome was based on the 11-item cognitive sub-scale of Alzheimer’s Disease Assessment Scale (ADAS-11), 14-item cognitive sub-scale of Alzheimer’s Disease Assessment Scale (ADAS-14), and the Alzheimer’s Disease Cooperative Study-Activities of Daily Living scale (ADCS-ADL). In the EXPEDITION 1 trail, the ADAS-11 score (higher scores signify worsening cognitive ability) was increased in both groups. Scores increased by 4.5 (95% CI, 3.3 to 5.8; P = 0.24) and 3.8 (95% CI, 2.5 to 5.0; P = 0.24) in the placebo verse treatment group, respectively; however, confidence intervals overlapped. Investigation with ADAS-14 which is considered a more sensitive indicator of cognitive ability in mild dementia showed similar results; the scores increased from baseline in both group with overlapping confidence intervals. The ADAS-14 scores for this study for placebo versus intervention were 5.8 (95% CI, 4.3 to 7.3, P = 0.09) and 4.5 (95% CI, 2.9 to 6.0, P = 0.09). ADCS-ADL (where lower scores indicate decreased ability) were lower in both the placebo and solanezumab-treated group at the end of 18 months, decreased by -8.7 (95% CI, -10.4 to -7, P = 0.64) versus -9.1 (95% CI, -10.9 to -7.4, P = 0.64) from baseline, respectively. However, confidence intervals again overlapped. These ambivalent findings were also replicated in the EXPEDITION 2 trial. The study’s authors theorized that possible efficacy would be derived in patients with very early disease and larger powered studies (p-values were greater than 0.05 in many of the investigated outcomes) [2].

A separate NEJM-published trial investigated bapineuzumab, another humanized anti-amyloid beta monoclonal antibody that binds to fibrillar, oligomeric, and monomeric forms. Results for this treatment were also lackluster. Two double-blind trials involved approximately 2500 patients with confirmed carriers and non-carriers of apolipoprotein E (APOE) epsilon4 allele—a lipoprotein associated with Alzheimer’s disease. Clinical outcome was measured again by the ADAS-11 and the Disability Assessment for Dementia (DAD), as well as CSF analysis and brain imaging in a random study subpopulation. Results showed no benefit in the intervention group versus placebo in both the carriers and non-carriers at doses of 0.5mg per kilogram and 1mg per kilogram every 13 weeks for 78 weeks. CSF showed decreased phospho-Tau concentration—a biomarkers of amyloid—and positron-emission tomographic amyloid imaging with Pittsburgh compound B (PIB-PET) showed decreased amyloid only in treated carriers of APOE epsilon4 allele. However, no clinical benefit or decreased MRI brain degeneration was obtained in comparison of the placebo versus treated carriers of APOE versus treated non-carriers. Also there were again observed increase rates of cerebral edema in carriers at higher doses of bapineuzumab. Per the study’s authors, amyloid accumulation probably starts many years before the onset of symptoms and anti-amyloid therapy after the onset of dementia may be too late in the clinical course to be of benefit [3].

So basically two NEJM articles said if you think you are developing dementia, it’s already too late for any possible benefit from these medical therapies. You should probably see your doctor…soon.

And if you wonder at the end of the day if all your efforts are actually helpful, well the literature shows mixed results on that too.

The Lancet published findings on global and regional stroke burden from 1990 to 2010 that compared incidence, mortality, disability and trends in high, low, and middle-income countries. To estimate global and regional burden of stroke during this period, researchers searched online medical databases for stroke related studies from 1990 to 2010 and applied statistical models that addressed incomplete epidemiological data first developed by he Global Burden of Diseases, Injuries, and Risk factors Study 2010 (GBD 2010). Results showed decreased age-standardized incidence of stroke by 12% (95% CI, 6 to 17) in high-income countries. Stroke incidence showed possible increase in both middle and low-income countries. In both middle and low-income countries, stroke incidence increased by 12% (95% CI, -3 to 22); however, findings were non-significant as the confidence interval crosses zero indicating chance of possible decreased rates. Stroke mortality rates decreased significantly in all countries. In high-income countries mortality decreased by 37% (95% CI, 31 to 41). In both middle-income and low-income countries, mortality decreased by 20% (95% CI, 15 to 30) This research also showed increased absolute numbers of stroke incidence, mortality, and morbidity concentrated in low and middle-income countries with significantly unequal geographic distribution—most predominately in Russia and its former satellite states, China, the Middle East, and southern Africa [4].

NEJM also published an investigation of diagnosis-associated adverse-event rates among Medicare patients with common medical conditions. Basically, researchers abstracted data from the Medicare Patient Safety Monitoring System (MPSMS) looking for adverse events in patients hospitalized for myocardial infarction, congestive heart failure, pneumonia, and conditions requiring surgery between the years 2005 and 2011. Adverse events included events associated with digoxin or anticoagulation, pressure ulcers, inpatient falls, hospital-acquired infections including ventilator-associated pneumonia, line/catheter-related, MRSA, Clostridium difficile colitis, intra-operative and post-surgical adverse events. Investigating a population of 61,523 patents, researchers determined that adverse events in myocardial infarction decreased from 5% to 3.7% over the 2005 to 2011 time period. Among inpatient congestive heart failure admissions, adverse events decreased from 3.7% to 2.7%. However, patients with pneumonia and those conditions requiring surgery had no significant change in adverse events. Rate of adverse events in patient admitted for pneumonia was 3.4 in 2005 and 3.5 in 2011 For conditions requiring surgical intervention, rate of adverse events was 3.2 in 2005 and 3.3 in 2011. This study suggested that although some inroads have been made in patient safety, there is still a disappointing lack of reductions across the board per the study’s authors [5].

Also in the literature this week:

1. The Mayo Clinic investigated risk stratification in patients hospitalized for community-acquired pneumonia based on age, preexisting conditions, vital signs, as well as laboratory and radiographic parameters that help place patients in 4 categories indicating risk of cardiac complications [6].

2. The Cleveland Clinic addressed obesity in the elderly, concluding that waist circumference may be a more appropriate gauge of weight status [7].

3. European researches investigated if there was a relationship between coronary events and exposure to polluted air. They found that populations in polluted ambient environments had increased risk of coronary events event when adjusted from sociodemographic and lifestyle risk factors [8].

4.This week the Annals of Internal Medicine investigated the risk of cardiovascular disease after giant-cell arteritis, finding that there is increased risk of MI. CVA, and PVD in both early and late follow-up periods [9].

And if this week has you down, think about the potential prospects for the last karaoke of the year that does not include Matt McNeill’s caterwauling: http://www.mirror.co.uk/3am/celebrity-news/beyonce-crashes-karaoke-party-kelly-3002843#.UuFrB6X0DQs

Dr. Luke O’Donnell is a 1st year resident at NYU Langone Medical Center

Peer reviewed by Arnab Ghosh, MD, Contributing Editor, Clinical Correlations

Image courtesy of Wikimedia Commons

References:

1. Devault AM, Golding GB, Waglechner N et al. Second-Pandemic Strain of Vibrio Cholerae from the Philadelphia Cholera Outbreak of 1849. New England Journal of Medicine 370(4); 334-340. 2014. http://www.nejm.org/doi/full/10.1056/NEJMoa1308663

2. Doody RS, Thomas RG, Farlow M et al. Phase 3 Trails of Solanezumab for Mild-to-Moderate Alzheimer’s Disease. New England Journal of Medicine 370(4); 311-321. 2014. http://www.nejm.org/doi/full/10.1056/NEJMoa1312889

3. Salloway S, Sperling R, Fox N et al. Phase 3 Trails of Bapineuzumab for Mild-to-Moderate Alzheimer’s Disease. New England Journal of Medicine 370(4); 322-333. 2014. http://www.nejm.org/doi/full/10.1056/NEJMoa1304839

4. Feigin VL, Forouzanfar MH, Krishnamurthi R et al. Global and Regional Burden of Stroke During 1990-2010: Findings from the Global Burden of Disease Study 2010. The lancet 383(9913); 245-255. 2014. http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(13)61953-4/fulltext

5. Wang Y, Eldridge N, Metersky ML et al. National Trends in Patient Safety for Four Common Conditions, 2005- 2011. New England Journal of Medicine 370(4); 341-351. 2014. http://www.nejm.org/doi/full/10.1056/NEJMsa1300991

6. Corrales-Medina VF, Taljaard M, Fine MJ et al. Risk Stratification for Cardic Complications in Patients Hospitalized for Community-Acquired Pneumonia. Mayo Clinic Proceedings 89 (1); 60-68. 2014. http://www.mayoclinicproceedings.org/article/S0025-6196(13)00927-0/abstract

7. Cetin DC, Nasr G. Obesity in the elderly: More complicated than you think. Cleveland Clinic Journal 81(1); 51-61. 2014. http://www.ccjm.org/content/81/1/51.abstract

8. Cesaroni G, Forastiere F, Stafoggia M et al. Long term exposure to ambient air pollution and incidence of acute coronary events: a prospective cohort study and meta-analysis in 11 European cohorts from the ESCAPE project. British Medical Journal 348. 2014. http://www.bmj.com/content/348/bmj.f7412

9. Tomasson G, Peloquin C, Mohammad A et al. Risk for Cardiovascular Disease Early and Late After a Diagnosis of Giant-Cell Arteritis: A Cohort Study. Annals of Internal Medicine 160(2). http://annals.org/article.aspx?articleid=1814422

 

Primecuts – This Week In The Journals

January 21, 2014

By Stephanie Gallitano, MD

Peer Reviewed

This week marks the 50-year anniversary since the Surgeon General released a report detailing health consequences of smoking. Since then, the evidence linking smoking with disease in nearly every organ system has been published. The number of premature deaths caused by smoking or exposure to secondhand smoke since 1965 now tops 20 million. This week’s new surgeon general’s report addresses some new diseases linked with smoking; we can now add colorectal and liver cancer, erectile dysfunction, diabetes, tuberculosis, age-related macular degeneration, ectopic pregnancy, rheumatoid arthritis and immune dysfunction to the never ending list of diseases. It also discusses effective methods of reducing smoking initiation and increasing smoking cessation- advertising by tobacco companies doesn’t work but taxation and enforcement of smoke-free indoor air policies does [1]!

In other public health news the American College of Emergency Physicians warned the public that our nation is failing to provide adequate emergency care. They issued a report card for every state and the nation as a whole which evaluated the conditions and policies under which emergency care is delivered. There were 136 measurements covering five categories, the largest percentage being attributable to “access to emergency care”. The nation received a rating of D- while New York ranks 13th in the nation, up from 21st place in 2009. Some of the strengths in NY leading to this advancement include requiring seatbelts and helmets to be worn and disaster preparedness with funds designated for disaster management. However the state’s malpractice and medical liability continues to challenge medical care. The state also has the highest occupancy rate in the nation, and the fourth longest average ED wait time (366 minutes) [2].

Tired of the blistering cold this year? Well some researchers are getting tired of treating genital blisters. For over 30 years, physicians have been using one drug class to treat patients with genital herpex simplex virus infections. The acyclovir-class of agents are nucleoside analogues that inhibit HSV DNA polymerase. While effective in reducing disease duration, viral shedding is still present and transmission to partners is only partially reduced. Additionally, immunosuppressed patients can have resistant viral strains. Pritelivir, a novel agent that inhibits the viral helicase-primase complex, thereby inhibiting DNA formation, may prove to be the next best option for infected patients. One hundred and forty-seven adults aged 18 and older with history of genital herpes and who were seropositive for HSV-2 were randomized in a parallel, double-blind, placebo-controlled study in a 1:1:1:1:1 ratio of different doses of Pritelivir v placebo. Exclusion criteria included infection with HIV, hepatitis B or C, pregnancy, immunosuppression, and treatment with medications that interfered with drug-metabolism. Patients either received a loading dose of 20mg followed by 5mg daily, a loading dose of 100mg followed by 25mg daily, a loading dose of 300mg followed by 75mg daily, or a weekly dose of 400mg. Patients submitted daily swabs of genital skin and mucosa for HSV detection and wrote symptoms in a diary. Pritelivir reduced viral shedding and the risk of genital lesions when given at a daily dose of 75mg daily or 400mg weekly when compared to placebo. No major adverse effects were noted in the subjects studied. Although more studies are needed to address efficacy in immunosuppressed populations and comparison to gold-standard therapy, this may be the precursor to future studies focusing on the benefit of using pritelivir in treating severe HSV infections and reducing sexual transmission [3].

Next time you are thinking about prescribing bisphosphonates for your patient you may have to think twice. A new retrospective cohort study from the VA looked at patients 65+ who had a known fracture and compared the risk of acute myocardial infarction in patients who took bisphosphonates and patients who did not have bisphosphonate exposure. Using a VA database, over 14,000 patients who had a known femoral or vertebral fracture were then assessed for bisphosphonate exposure. The primary outcome was incident acute myocardial infarction. Bisphosphonate use was associated with an increased risk of acute myocardial infarction (HR 1.38, CI 1.08-1.77, P=0.01). This finding was especially shocking in light of the hypothesis that bisphosphonates were protective against cardiovascular disease. Bisphosphonates are thought to inhibit an enzyme downstream of the site of statins. They also inhibit hydroxyapatite crystal aggregation in vitro and have been shown to have antiatherogenic properties. However, this study is limited by it being retrospective and having limited data available. There also may be a selection bias in that patients requiring bisphosphonates may have higher baseline risk of cardiovascular disease [4].

Still confused about what advice you should provide your patients regarding weight loss when they are diabetic? Tobias et al just published a retrospective cohort study involving 11,427 diabetic participants from the Nurses’ Health Study and the Health Professionals Follow-up Study, looking at the association between Body Mass Index (BMI) and death from any cause. The study also adjusted for smoking as smoking often leads to decreased body weight but increased risk of death. Mean follow up time was 15.8 years, over which time 3083 deaths were observed. A J-shaped association between BMI and all-cause mortality was observed, with those participants in the BMI 22.5-24.9 BMI category having lower mortality than those participants with BMI 18.5-22.4 (HR 1.29, 95%CI, 1.05-1.59) or 24.9 and above. Smoking status significantly modified the results. For those participants who never smoked, a linear trend was seen. However among those participants who did smoke, a J-shaped trend in all-cause mortality was observed. Significant effect modification was also seen with age at diagnosis of diabetes- a linear relationship was seen between adults diagnosed with diabetes at age younger than 65. However, a direct linear trend was only appreciated in those patients who were diagnosed at age 65 or older who never smoked. Those patients who had smoked had a significantly increased risk of death in the lowest BMI category. This study demonstrates that diabetic patients should aim to maintain a BMI of 22.5-24.9 [5].

Other research in the news:

1. Can eastern and western medicine meet? A randomized control trial demonstrated a reduction in progression of impaired glucose tolerance to type 2 diabetes mellitus in patients taking Tianqi, a combination of 10 Chinese herbal medications. Absolute risk reduction in progression to T2DM was 11% amongst patients taking Tianqi [6].

2. There may be hope for patients with Parkinson’s disease in the form of a viral vector that allows for continuous dopamine production. All 15 patients enrolled in this phase ½ study experienced significant improvement in motor scores at 6 and 12 months compared to baseline scores [7].

3. For patients presenting with ruptured abdominal aortic aneurysm, endovascular repair is comparable to open repair in terms of 30-day mortality and cost. Women however, may have improved outcomes from endovascular strategy [8].

Dr. Stephanie Gallitano is a 1st year resident at NYU Langone Medical Center

Peer reviewed by Arnab Ghosh, MD, Contributing Editor, Clinical Correlations

Image courtesy of Wikimedia Commons

References:

1. http://www.surgeongeneral.gov/library/reports/50-years-of-progress/exec-summary.pdf Accessed 1/18/2014 @ 0830

2. http://www.emreportcard.org/Content.aspx?id=534 Accessed 1/17/2014@ 1630

3. Wald A, Corey L, Timmler B, et al. Helicase-primase inhibitor pritelivir for HSV-2 infections. N Engl J Med. 2014 Jan 16;370(3):201-10.  http://www.nejm.org/doi/full/10.1056/NEJMoa1301150

4. Pittman CM, Davis LA, Zeringue AL, et al. Myocardial Infarction Risk Among Patients with Fractures Receiving Bisphosphonates. Mayo Clinic Proceedings.2014 Jan;89(1):43-51.  http://www.mayoclinicproceedings.org/article/PIIS0025619613008732/abstract

5. Tobias DK, Pan A, Jackson CL, et al. Body-Mass Index and Mortality among Adults with Incident Type 2 Diabetes. N Engl J Med. 2014 Jan 16;370(3):233-244.  http://www.nejm.org/doi/full/10.1056/NEJMoa1304501

6. Lian F, Li G, Chen X et al. Chinese Herbal Medicine Tianqi Reduces Progression from Impaired Glucose Tolerance to Diabetes: A Double-Blind, Randomized, Placebo-Controlled, Multicenter Trial. J Clin Endocrinol Metab. 2014 Jan 16. Epub viewed Jan 17, 2014.

7. Palfi S, Gurruchaga JM, Ralph GS. Long-term safety and tolerability of ProSavin, a lentiviral vector-based gene therapy for Parkinson’s disease: a dose escalation, open-label, phase ½ trial. Lancet. 2014 Jan 9. Epub viewed Jan 18, 2014.

8. Investigators IT. Endovascular or open repair strategy for ruptured abdominal aortic aneurysm: 30 day outcomes from IMPROVE randomized trial. BMJ. 2013 Jan 13;348. Epub viewed Jan 16, 2014.  http://www.bmj.com/content/348/bmj.f7661?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+bmj%2Fresearch+(Latest+BMJ+Research)

 

Primecuts – This Week In The Journals

January 13, 2014

By Arnab Ghosh, MD

Peer Reviewed

This week’s Clinical Correlations begins with email revelations implicating the administration of New Jersey Governor Chris Christie in the closure of traffic lanes across the George Washington Bridge, thus making one of the country’s busiest thoroughfares log-jammed with traffic for days this previous summer.

Earlier this week emails were released from high-level public servants in the Christie administration which suggest the secretive, planned closure of traffic lanes in the borough of Fort Lee, whose mayor had previously refused to endorse the Governor during the recent gubernatorial elections. For the larger-than-life second term Governor, viewed as a serious Republican candidate for the 2016 Presidential election, these revelations are seen to have the potential to cause considerable harm to his future political aspirations. Fighting against accusations of vindictiveness, pettiness and the appearance of being a ‘bully’, Gov. Christie held a two-hour news conference expressing his own disappointment at his staff, asking the people of New Jersey for his forgiveness, and summarily firing the implicated members of his administration. With the US Attorney in New Jersey looking into the matter on behalf of the Federal Government, how this affects the short list of Republican candidates for the 2016 Presidential election remains to be seen.

In other (less controversial) news, this week the Journal of the American Medical Association (JAMA) celebrated the anniversary of the publication of the 1964 landmark surgeon general report entitled Smoking and Health with smoking cessation-related research. One study sought to empirically assess the effect of combination pharmacotherapies in tobacco-dependent patients seeking to quit smoking [1]. Testing the hypothesis that combination varenicline/bupropion –sustained release would serve better than varenicline alone in tobacco cessation at 12 weeks (determined by biochemical confirmation and self report), researchers randomized 506 participants into two arms in a blinded, placebo-controlled multicenter trial.

Participants were required to be motivated to want to quit smoking, be at least 18 years of age, and to smoke more than 10 cigarettes per day for at least 6 months. Exclusion criteria included pregnant or lactating women, those with unstable medical conditions including angina, renal failure and seizures, allergies to either varenicline or bupropion, or evidence of suicidality or depression.

Analysed according to intention-to-treat protocols, it was reported at 12 weeks that 53% of the intervention group (combination varenicline/bupropion SR) had achieved prolonged smoking cessation (defined as no smoking from 2 weeks after a set quit date) and 56.2% had achieved 7 day point-prevalence smoking abstinence (defined as no smoking within the past 7 days of testing). This was compared to 43.2% in the varenicline monotherapy group for prolonged smoking cessation, and 48.6% in the 7 day point-prevalence smoking abstinence (OR, 1.49; 95% CI 1.05-2.12, p=0.03, and OR 1.36; 95% CI 0.95-1.93, p=0.09). At 26 weeks, prolonged smoking cessation remained statistically significant in the combination group, but this was lost at 52 weeks. Of note, patients receiving combination pharmacotherapy reported more symptoms of anxiety, depression and flatulence.

Based on these results, it seems like the holy grail of smoking cessation is still beyond the reach of the medical profession. While the combination of varenicline/bupropion is encouraging in the short term, it seems longstanding measures, including nicotine replacement and smoking counseling remain important factors in the sustainment of cessation.

This week in the Green Journal, further evidence for the use of digoxin in heart failure to reduce readmissions was published [2]. As part of a series of studies published out of the University of Alabama and the Alabama Heart Failure Project, a retrospective cohort study involving data from 921 patients discharged on digoxin after being hospitalized with heart failure (mean age 75 years, 55% female, 25% African-American, 58% with an ejection fraction of less than 45% , 69% of an ACEI or ARB, 32% on a beta-blocker, 18% on potassium-sparing diuretics) were matched to cohort of 921 not taking digoxin (with similar baseline characteristics and pharmacology profiles).

Using the primary outcome of all cause 30-day hospital readmission, 17% of the digoxin cohort were readmitted as compared to 22% of the matched non-digoxin group (HR 0.77, 95% CI 0.63-0.95). Furthermore, this benefit was particularly noted in those patients with ejection fractions less than 45%, persisted over the following 12 months, and did not change all-cause mortality between the two groups. Like the studies preceding it [4], this well-designed study points to the usefulness of digoxin in heart failure patients, particularly amongst a population of patients known to be susceptible to exacerbations and readmissions.

In separate news, the New England Journal of Medicine published data suggesting the beneficial use of a surgically implanted upper airway stimulation device as a novel therapy in the treatment of obstructive sleep apnea for those patients unable to tolerate continuous positive airway pressure (CPAP). In a multicenter, prospective uncontrolled cohort study with 126 participants (83% men, average age 54.5, average body mass index 28.4), there was both statistically significant reduction in the median 12 month apnoea-hypopnoea index (AHI) of 68% ( p< 0.001), as well as subjective improvement in sleep as determined by the Epworth Sleepiness Scale score (11 to 6, p < 0.001)) and Functional Outcomes of Sleep Questionnaire (FOSQ) (14.6 to 18.2, p< 0.001). This suggests that for appropriate patients suffering from OSA who do not tolerate CPAP, upper airway stimulation may be an alternative means of therapy.

Of interest to physicians and residents themselves, Mayo Clinic Proceedings published this week a study examining the effects of an incentivized exercise program on rates of burnout, quality of life and physical activity on fellows and residents [5]. Using survey tools to assess the amount of physical activity, quality of life and burnout, all residents and fellows at the Mayo Clinic were invited to participate in a 12 week voluntary, self directed exercise program. Fifty-nine percent of residents and fellows participated in the study, of which only 23% enrolled in the exercise program. Compared to non-enrollees, those enrolled in the study met the standard US Department of Health recommendation for exercise (48% vs 23%, p < 0.001), their quality of life was better (P < 0.001), although burnout rates were not statistically significantly reduced (24% vs 29%, p=0.17).

In other news:

1. Rates of influenza have increased across 25 states in the Union [6]. The strain H1N1 2009 seems to be predominating in the cases being seen.

2. For the fourth consecutive year, it seems that growth in healthcare spending nationally has decreased (3.7% in 2012), in line with a decrease in Gross Domestic Product allocated to healthcare (from 17.3 to 17.2%), while the nominal GDP increased 4%.

Dr. Arnab Ghosh is a 3rd year resident at NYU Langone Medical Center

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

Image of the  cover of the 1964 landmark surgeon general report entitled Smoking and Health

References:

1. Ebbert J, Hatsukami D, Croghan I et al Combination Varenicline and Bupropion SR for Tobacco-Dependence Treatment in Cigarette Smokers: A Randomized Trial JAMA. 2014;311(2):155-163  http://jama.jamanetwork.com/article.aspx?articleid=1812959

2. Ahmed A, Bourge R, Fonarow G et al. Digoxin Use and Lower 30-day All-cause Readmission for Medicare Beneficiaries Hospitalized for Heart Failure. Am J Medicine (2014) 127,61-70  http://www.amjmed.com/article/S0002-9343(13)00786-9/abstract

3. 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  http://www.amjmed.com/article/S0002-9343(13)00137-X/abstract

4. Strollo P, Soose R, Maurer J et al. Upper-Airway Stimulation for Obstructive Sleep Apnea. NEJM. 370;2 139-149   http://www.nejm.org/doi/full/10.1056/NEJMoa1308659

5. Weight C, Sellon J, Lessard-Anderson C et al. Physical Activity, Quality of Life, and Burnout Among Physician Trainees: The Effect of a Team-Based, Incentivized Exercise Program. Mayo Clin Proc. 2013 Dec; 88(12):1435-1443  http://www.researchgate.net/publication/259107687_Physical_activity_quality_of_life_and_burnout_among_physician_trainees_the_effect_of_a_team-based_incentivized_exercise_program

6. http://www.cdc.gov/flu/weekly/summary.htm Accessed 1/11/2014 @0700

7. Martin A, Hartman M, Whittle L at al. National Health Spending in 2012: Rate of Health Spending Growth Remained Low for the Fourth Consecutive Year. Health Aff (Milwood) Jan 06 2014; 33: 67-77 http://www.ncbi.nlm.nih.gov/pubmed/24395937

 

 

 

Primecuts – This Week In The Journal

January 6, 2014

By Gregory Katz, MD

Peer Reviewed

The beginning of 2014 marks not only a new calendar year, but a new era of American health care with the opening of the Affordable Care Act (ACA) health insurance exchanges. While the majority of media coverage about the ACA has been devoted to changing insurance policies and concern about systemic upheaval, the expansion of Medicaid has been largely ignored by the popular press. Despite its lack of sexiness as a topic of newspaper coverage, the health effects of Medicaid expansion are being increasingly well-described by researchers. Last summer, we got our first peek at results from the Oregon Health Study Group, which is investigating the effects of the 2008 Oregon lottery that randomly allocated a limited number of expanded Medicaid slots to eager residents. The Oregon Health Study has permitted a rare prospective randomized trial on the both the health and health care utilization effects of Medicaid expansion. The initial results published in the New England Journal of Medicine found that while increasing Medicaid access did not have a statistically significant effect on quantitative outcomes like blood pressure or hemoglobin A1C, incidence of depression and catastrophic out-of-pocket medical expenditures both decreased [1].

Now the Oregon Health Study Group is back with a new look at the effect on health care utilization of expanding Medicaid. Their recently published article in Science evaluated emergency room usage by new Medicaid recipients and found an increase of 0.41 ED visits per person over 18 months (a 40% increase) for those with newly acquired Medicaid coverage [2]. The increase in ED visits for patients occurred along with a self-reported increase in access to primary care, begging the question of why patients would increasingly visit the emergency room if they also report better access to primary care physicians. An article from Health Affairs earlier in 2013 found that the problem is multifactorial: lower income patients have a harder time getting to the doctor during normal business hours, they perceive the hospital to provide better care than an outpatient visit, and they associate office visits with a greater total time cost because of the frequency of specialist referrals [3]. These new data from the Oregon Health Study Group continue to deliver the message that health insurance reform (i.e. who pays for health care) is often much less important for both outcomes and expenditures than health care delivery reform.

Part of the impetus for passing the ACA was the growing burden of health care costs on our economy. Comparative effectiveness research that allows us to assess the effectiveness of expensive and invasive procedures relative to noninvasive – and less expensive – medical management strategies continues to be a vital part of health care research. We learned last week in Primecuts that many knee surgeries for partial meniscal teares are no more effective than sham procedures [4]. Piggybacking on this theme are new data from the CORAL investigators demonstrating that there is no marginal benefit to be achieved from renal artery stenting in patients with atherosclerotic renal artery stenosis on top of optimal medical therapy [5].  Stenting did not reduce mortality, need for hemodialysis, myocardial infarction, stroke, or new congestive heart failure in patients with renal artery stenosis and hypertension or chronic kidney disease. These data echo results from studies such as the COURAGE trial that continue to recognize that the pathophysiology of vascular disease and its associated morbidities is more complicated than simply decreased blood flow [6]. These results from the CORAL investigators will avoid unnecessary and invasive procedures to open up stenosed renal arteries.

In other news, the TEAM-AD VA investigators found that vitamin E supplementation for patients with mild to moderate Alzheimer’s disease helped participants retain the ability to carry out activities of daily life and reduced caregiver burden by about 2 hours per day [7]. Patients in this trial were randomized to either 2000IU of vitamin E daily, 20mg of memantine, a combination of the two, or placebo. No significant difference was observed with memantine compared to placebo. Unfortunately, disease progression in terms of cognitive decline was not affected with either vitamin E supplementation or memantine. Clinicians should be careful before extrapolating these results to any patients other than those with mild to moderate Alzheimer’s as high dose vitamin E supplementation may be also be associated with an increased risk of cancer [8].

Other reading this week:

A study this week in the Lancet looked at the cost effectiveness of HAART therapy with different types of clinical monitoring [9]. Authors concluded that while viral load monitoring provides the greatest reduction in morbidity and mortality, its high cost limits its utility when resources are increasingly limited. Researchers advocate expanding drug therapy and only monitoring viral loads after improved HAART access is obtained.

We definitively learned this week something many of us have long suspected: texting while driving is bad for your health. Researchers in the New England Journal investigated crashes and near crashes for both experienced and novice drivers, finding that cell phone use is hazardous, increasing the risk for all drivers [10].

For those of us who struggle with convincing our patients of the benefit of many important medical therapies, here is some encouraging news on the benefits of continuous positive airway pressure: treating patients with sleep apnea may help to improve their golf games [11]. Interestingly, researchers found “unusually high” treatment adherence in this study. This should reinforce the idea that finding ways to make medical treatment relevant to a patient’s life is a vital part of an excellent clinician’s job description.

Dr. Gregory Katz is a 2nd year resident at NYU Langone Medical Center

Peer reviewed by Brian Greet, MD, Chief Medical Resident at NYU Langone Medical Center, Associate Editor, Clinical Correlations

Image courtesy of Wikimedia Commons

References:

1. Baicker K, Taubman SL, Allen HL et al. The Oregon Experiment — Effects of Medicaid on Clinical Outcomes. N Engl J Med 2013; 368:1713-1722  http://www.ncbi.nlm.nih.gov/pubmed/23635051

2.  Taubman SL, Allen HL et al. Medicaid Increases Emergency-Department Use: Evidence from Oregon’s Health Insurance Experiment. Science 2 January 2014: science.1249341v1-1249341.  http://www.ncbi.nlm.nih.gov/pubmed/24385603

3. Kangovi S, Barg FK, Carter T, et al. Understanding Why Patients Of Low Socioeconomic Status Prefer Hospitals Over Ambulatory Care. Health Aff July 2013 vol. 32 no. 7 1196-1203  http://www.ncbi.nlm.nih.gov/pubmed/23836734

4.  https://www.clinicalcorrelations.org/?p=7181

5.  Cooper CJ, Murphy TP, Cutlip DE, et al. Stenting and Medical Therapy for Atherosclerotic Renal-Artery Stenosis. N Engl J Med 2014; 370:13-22  http://www.nejm.org/doi/full/10.1056/NEJMoa1310753?query=featured_cardiology

6.  Boden WE, O’Rourke RA, Koon KT, et al. Optimal Medical Therapy with or without PCI for Stable Coronary Disease. N Engl J Med 2007; 356:1503-1516

7.  Dysken MW, Sano M, Asthana S, et al. Effect of Vitamin E and Memantine on Functional Decline in Alzheimer Disease: The TEAM-AD VA Cooperative Randomized Trial. JAMA.2014;311(1):33-44.  http://jama.jamanetwork.com/article.aspx?articleid=1810379

8.  Slatore CG, Littman AJ, Au DH, Satia JA, White E Long-term use of supplemental multivitamins, vitamin C, vitamin E, and folate does not reduce the risk of lung cancer. Am J Respir Crit Care Med. 2008 Mar 1;177(5):524-30.  http://www.ncbi.nlm.nih.gov/pubmed/17989343

9. Keebler D, Revill P, Braithwaite S, et al. Cost-effectiveness of different strategies to monitor adults on antiretroviral treatment: a combined analysis of three mathematical models. The Lancet Global Health, Volume 2, Issue 1, Pages e35 – e43,  http://www.thelancet.com/journals/langlo/article/PIIS2214-109X(13)70048-2/abstract

10.  Klauer SG, Guo F, Simons-Morton BG, et al. Distracted Driving and Risk of Road Crashes among Novice and Experienced Drivers. N Engl J Med 2014; 370:54-59  http://www.nejm.org/doi/full/10.1056/NEJMsa1204142

11. Benton ML; Friedman NS. Treatment of obstructive sleep apnea syndrome with nasal positive airway pressure improves golf performance. J Clin Sleep Med 2013;9  http://www.ncbi.nlm.nih.gov/pubmed/24340283

 

Primecuts – This Week In The Journals

December 30, 2013

By Monica Gupta, MD

Peer Reviewed

Welcome to the final Clinical Correlations post of the year!

As 2013 comes to a close, it’s a time to reflect on the year that has passed. Here at NYU, 2013 was a triumphant year as it marked the return of Bellevue, Tisch, and the Manhattan VA after Superstorm Sandy took its toll. Now with that in the past, we embrace the new adventures that await us in 2014 – another year to strive to deliver excellent patient care with the most up-to-date evidence-based medicine.

As for the “New Year” in the medicine world, July has always been a special time in teaching hospitals. It is the time when bright-eyed, freshly minted doctors enthusiastically arrive on the wards to save lives. “The July effect” has been investigated with many studies that have shown a relatively small, yet statistically significant, increase in mortality at the beginning of the residency year. A recent retrospective observational study in Circulation by Jena et al. looked at “the July effect” on inpatient mortality after acute myocardial infarction (MI) [1]. The Nationwide Inpatient Sample was used to identify a group of patients admitted to U.S. hospitals with acute MI during May and July from 2002 to 2008. All-cause inpatient mortality was assessed with the hypothesis that patients admitted with acute MI to teaching hospitals in July would experience lower rates of percutaneous coronary intervention or higher rates of bleeding complications as compared to non-teaching hospitals in July. Interestingly, this study concluded that high-risk acute MI patients experience similar outcomes in July regardless of hospital setting. There was also no statistically significant difference in outcomes for low-risk patients in teaching hospitals versus non teaching hospitals in July. However, it was noted that high-risk acute MI patients do experience lower adjusted mortality in teaching hospitals in May as compared to July, (18.8% in May, 95% confidence interval [CI] 16.9%-20.7%; 22.7% in July, 95% CI 20.6%-24.8%; p= 0.006) likely attributable to the increased relative experience of the housestaff at that time of year.

Also in Circulation this week, a study by Barbanti et al. examined the impact of pre-operative moderate to severe mitral regurgitation (MR) on outcomes after transcatheter aortic valve replacement (TAVR) and surgical aortic valve replacement (SAVR) [2]. This analysis looked at patients enrolled in cohort A (high risk patients) of the PARTNER trial, which studied those with severe symptomatic aortic stenosis undergoing TAVR or SAVR. In this analysis, SAVR patients with moderate or severe MR had significantly higher 2-year all cause mortality compared to those with mild or less MR and had significantly higher cardiovascular mortality as well. Specifically, SAVR patients with moderate/severe MR trended towards higher mortality at 30 days compared with patients with no/mild MR (13.6% vs 7.1%, hazard ratio [HR] 2.01; 95% CI, 0.87-4.67; p= 0.09) as well as a significantly higher mortality rate between 30 days and 2 years (41.4% vs 22.4%, HR 1.95; 95% CI, 1.16-3.27; p=0.01). Of note, there was no significant mortality difference in TAVR patients with moderate/severe MR as compared to mild/no MR both during the first 30 days and from 30 days to 2 years. This suggests better long term outcomes are associated with TAVR as compared to SAVR for those with combined aortic and mitral valve disease.

Being that the New Year is right in the middle of flu season, it’s the perfect time for new light to be shed on the efficacy of the flu vaccine for children. In the New England Journal of Medicine this week, a multinational, phase 3, observer-blinded study assessed the efficacy of a candidate inactivated quadrivalent influenza vaccine [3]. Current trivalent vaccines contain one influenza B virus lineage and may not be effective against viruses of the other B lineage, therefore resulting in possible inadequate protection by the vaccine. The aim of this study was to assess the efficacy of a candidate quadrivalent vaccine (QIV), which contains both B lineages, for the prevention of influenza A or B in children ages 3 to 8 years. This study used the end point of any influenza, as well as the additional end point of moderate to severe influenza, as this additional end point may be more clinically significant. The detection of influenza A or B was done with nasal or throat swabs, and confirmed with real-time polymerase chain reaction assays. Positive samples were then further tested with cell culturing. Moderate to severe disease was defined as temperature greater than 39 degrees , physician confirmed acute otitis media, lower respiratory tract illness, or extrapulmonary complications. This study ultimately showed that the QIV has an efficacy of 55% against influenza of any severity. Among children with moderate to severe disease, the QIV, as compared to the control vaccine (hepatitis A vaccine), was associated with the following: 69% fewer medical visits, 75% fewer hospitalizations, 77% fewer absences from school. Though two of this study’s strengths were that it was conducted over 3 global regions and that it used two methods to identify cases of influenza, it must be noted that it was conducted only during one flu season and was compared to the hepatitis A vaccine as opposed to standard influenza vaccines. However, based on the efficacy of the QIV as compared to the control, this vaccine appears as though it could be useful in the event that both B lineages are circulating during a flu season or if there is an unexpected shift from one lineage to another.

 

To all of our readers, here’s to wishing you a happy and healthy 2014!

 

Additional reading:

1. In a New England Journal study, patients with symptoms of a degenerative medial meniscus tear were randomized to arthroscopic partial meniscectomy or sham surgical procedure. It was found in a multicenter, randomized, double-blind study that the outcomes after arthroscopic partial meniscectomy were no better than those after a sham surgical procedure.

Sihvonen R, Paavola M, Malmivaara A, et al. Arthroscopic Partial Meniscectomy versus Sham Surgery for a Degenerative Meniscal Tear. N Engl J Med. 26 Dec 2013. 369: 2515-2524. http://www.nejm.org/doi/full/10.1056/NEJMoa1305189?query=featured_home

 

2. In JAMA this week, granulocyte-macrophage colony-stimulating factor (GM-CSF) was investigated for improving exercise capacity in patients with intermittent claudication. In a double blind, placebo controlled study, 159 patients with intermittent claudication were randomized to receive 4 weeks of subcutaneous injections of GM-CSF 3 times a week, or placebo, in conjunction with walking to claudication daily. Therapy with GM-CSF 3 times a week did not improve treadmill walking performance at the 3 month follow-up mark.

Poole J, Mavromatis K, Binongo JN. Effect of Progenitor Cell Mobilization With Granulocyte-Macrophage Colony-Stimulating Factor in Patients with Peripheral Artery Disease. JAMA. 25 Dec 2013. 310 (24): 2631-2639. http://jama.jamanetwork.com.ezproxy.med.nyu.edu/article.aspx?articleid=1780018

 

3. In the Lancet this week, a study showed that both baseline daily physical activity and change in daily ambulatory activity were associated inversely with the risk of cardiovascular events in patients with impaired glucose tolerance at high cardiovascular risk.

Yates T., Haffner SM, Schulte PJ, et al. Association Between Change in Daily Ambulatory Activity and Cardiovascular Events in People with Impaired Glucose Tolerance (NAVIGATOR trial): a Cohort Analysis. The Lancet. 20 Dec 2013. (13): 62061-9. http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(13)62061-9/fulltext#article_upsell

 

Dr. Monica Gupts is a 2nd year resident in internal medicine, at NYU Langone Medical Center

Peer reviewed by Dr. Matthew Vorsanger, Associate Editor, Clinical Correlations


References

1. Jena A, Sun EC, Romley JA. Mortality Among High-Risk Patients with Acute Myocardial Infarction Admitted to US Teaching-Intensive Hospitals in July. Circulation. 24 Dec 2013. 128: 2754- 2763. http://circ.ahajournals.org.ezproxy.med.nyu.edu/content/128/25/2754.full

2. Barbanti M, Webb J, Hahn R, et al. Impact of Preoperative Moderate/Severe Mitral Regurgitation on 2-Year Outcome After Transcatheter and Surgical Aortic Valve Replacement. Circulation. 24 Dec 2013. 128: 2776-2784. http://circ.ahajournals.org.ezproxy.med.nyu.edu/content/128/25/2776.full

3. Jain VK, Rivera L, Zaman K, et al. Vaccine for Prevention of Mild and Moderate-to-Severe Influenza in Children. N Engl J Med. 26 Dec 2013; 369: 2481-2491. http://www.nejm.org.ezproxy.med.nyu.edu/doi/full/10.1056/NEJMoa1215817#t=articleMethods

 

 

 

 

 

 

Primecuts – This Week In The Journals

December 23, 2013

By Preethi Prasad, MD

Peer Reviewed

This week, Christmas is finally on its way, and the city is alive with festive cheer. Children are excitedly anticipating a visit from Santa Claus, while adults are scrambling to do last-minute Christmas shopping. In addition to sipping eggnog and enjoying the holidays, many Americans are also using this time to focus on their health as Monday, December 23rd is the deadline for most to sign up for health insurance that starts on January 1st.

For some people, traveling home for Christmas requires a Trans-Atlantic flight, and it is important to be aware of the increased risk of pulmonary embolism (PE) from prolonged immobility. Computed tomographic pulmonary angiography (CTPA) is the primary imaging modality used to diagnose PE. An article in Chest explored the utility of using CTPA to establish alternative diagnoses such as pneumonia, pleural effusion, tumor, atelectasis, bronchiolitis, pericardial effusion, chronic obstructive pulmonary disease (COPD), and heart failure [1]. The 203 patients in the study were all classified as likely to have PE based on Wells criteria, and treating physicians evaluated the patients and considered alternative diagnoses prior to imaging. Ultimately after imaging, 39 patients (19%) were diagnosed with PE, 61 (30%) had normal CTPA, and alternative diagnoses were found in 88 (43%). These alternative diagnoses included pneumonia, pleural effusions, and tumors. In 56 (28%) of these 88, the alternative diagnoses were thought to account for the initial presenting signs and symptoms. 19 of the 56 (8.8%) had findings that were unsuspected prior to imaging. In 11 patients (5.4%), the abnormalities on imaging resulted in further diagnostic testing, such as bronchoscopy, thoracentesis, sputum culture, or magnetic resonance imaging. In 10 patients (4.9%), the results from the imaging had therapeutic consequences, specifically antibiotics, diuretics, or corticosteroids. Despite the lack of guidelines on scanning patients with a low pretest probability for PE, clinicians often use CTPA in the hope that it will help find an alternative diagnosis. This study advises against the liberal use of imaging due to the relatively low yield of therapeutic consequences. As clinicians, we should primarily use CTPA in patients with a sufficiently high pretest probability for PE and not to establish alternative diagnoses.

Under the Affordable Care Act, uninsured patients with pre-existing conditions, such as asthma and COPD, will no longer be denied coverage. An article in Chest looked into the risk of pneumonia and lower respiratory tract infections (LRTI) in asthma patients on inhaled corticosteroids (ICS) [2]. The study enrolled 6857 patients with pneumonia and LRTI. The results showed that fluticasone propionate was associated with a higher risk of pneumonia or LRTI (odds ratio [OR] 1.20 95% confidence interval [CI] 1.06-1.35. After adjusting for confounding variables, 1.7% of the patients were prescribed high doses of ICS (>1000 ug), and these patients were 2.04 times more likely to have pneumonia or LRTI (95% CI 1.59-2.64) with the effect being strongest for pneumonia. This study will be useful in practice, as we should be vigilant of the doses of ICS and use the lowest dose necessary to control a patient’s symptoms due to the secondary risk of developing pneumonia and LRTI .

Ventilator-associated pneumonia (VAP) results in prolonged intensive care unit stays and a significant economic burden, costing several thousands of health care dollars per patient [3]. A systematic review in Chest explored the appropriate duration of antibiotic regimens in patients with ventilator-associated pneumonia with the hypothesis that using shorter regimens may decrease resistance and adverse events [4]. Ultimately, four randomized control trials were used in the study, encompassing a total of 883 patients with VAP who were either treated with a short course of antibiotics (7-8 days) or a long course (10-15 days). The primary outcomes were 28-day mortality, antibiotic-free days, and relapses. The results showed that there was no difference in mortality in the two groups (fixed effect model [FEM] OR=1.20; 95% CI, 0.84-1.72 P=0.32). Although there was no statistically significant difference in relapses amongst the two treatment arms, there was a trend to lower relapses in the longer treatment group (FEM: OR=1.67 95% CI, 0.99-2.83 P=0.06). The primary conclusion from the study was that there was no difference in mortality between the short and long treatment arms. Of note, the relapses in the studies were mostly due to nonfermenting gram negative bacilli (NFGNB), for which relapses are common [5]. The article suggests monitoring serum biomarkers such as procalcitonin in conjunction with short-course regimens, particularly in patients with NFGNB infections. Although there was no difference in mortality, in practice, it is still important to balance the pros and cons of the duration of antibiotics until more definitive data becomes available through targeted trials.

With the advent of affordable health care, it is expected that there will be more elective noncardiac surgeries and procedures performed in an aging population with cardiac comorbidities. In Chest, a recent systematic review was published describing clinical practice guidelines on the perioperative management of antiplatelet therapy in patients with stents who require noncardiac surgery [6]. Managing patients with coronary stents who require noncardiac surgery is particularly challenging due to the need to balance the risk of major adverse cardiovascular events (MACE) against the risk of bleeding. Overall, patients with coronary stents have an 8-10% risk of developing MACE during noncardiac surgery compared to 1-5% in the general population without stents [7]. Ultimately, 11 studies were included in the review, but there were no Grade 1A or 1B recommendations from any of the articles. The guidelines advised delaying elective noncardiac surgery for at least 4 weeks after bare-metal stent placement and 6 months after drug-eluting stent placement. Aspirin should be continued whenever possible, and both aspirin and clopidogrel should be continued for urgent procedures. If clopidogrel were to be discontinued due to increased bleeding risk, 8 of the studies recommended the continuation of aspirin. If aspirin and/or clopidogrel were to be discontinued prior to surgery, four articles recommended stopping the antiplatelet agents at least 5 days prior to surgery, but there was no true consensus. Three studies suggested resuming antiplatelet therapy within 24 hours after surgery. There was no true consensus about the role for bridging agents amongst the 11 articles. The clinical implications of this article are the following: it is recommended to defer elective noncardiac surgery for at least 4 weeks after bare-metal stent placement and 6 months after drug-eluting stent placement and continue aspirin perioperatively in most patients and dual antiplatelet therapy in high risk patients unless precluded by high bleeding risk. There is still no established consensus on when to discontinue the medications or when to resume them after surgeries. The article highlights the lack of high quality evidence in this area and the need for further randomized control trials and cohort studies.

 

Additional Articles:

1. This study was a randomized control trial that investigated whether oral high-dose multivitamins and minerals would reduce cardiovascular events in patients after myocardial infarction. The primary endpoints were mortality, recurrent MI, stroke, angina leading to hospitalization, and coronary revascularization. Ultimately, the results showed that vitamins and minerals did not statistically significantly reduce these events.

Lamas GA, Boineau R, Goertz C, et al. Oral High-Dose Multivitamins and Minerals After Myocardial Infarction: A Randomized Trial. Annals of Internal Medicine. 2013 Dec;159(12):797-805. http://annals.org/article.aspx?articleid=1789248

 

2. This study was also a randomized control trial that explored the use of multivitamins in improving cognitive function in men. The study involved 5947 male physicians above the age of 65. Ultimately, there were no statistically significant cognitive benefits from multivitamin supplementation that were shown.

Grodstein F, O’Brien J, Kang JH, et al. Long-Term Multivitamin Supplementation and Cognitive Function in Men: A Randomized Trial. Annals of Internal Medicine. 2013 Dec;159(12):806-814. http://annals.org/article.aspx?articleid=1789250

 

3. The ROSE acute heart failure randomized trial investigated the use of low-dose dopamine and nesiritide in patients with acute heart failure to enhance decongestion and preserve renal function. With respect to 72-hour cumulative urine volume, cystatin C level, and decongestion, both medications were shown to have no statistically significant effect compared to placebo.

Chen HH, Anstrom KJ, Givertz MM et al. Low-dose dopamine or low-dose nesiritide in acute heart failure with renal dysfunction: the ROSE acute heart failure randomized trial. JAMA. 2013 Dec 18;310(23):2533-43. http://jama.jamanetwork.com/article.aspx?articleid=1779722

 

Dr. Preethi Prasad is a 2nd year resident in internal medicine, at NYU Langone Medical Center

Peer reviewed by Dr. Matthew Vorsanger, Associate Editor, Clinical Correlations


References

1. Van Es J, Douma RA, Schreuder SM, et al. Clinical Impact of Findings Supporting an Alternative Diagnosis on CT Pulmonary Angiography in Patients With Suspected Pulmonary Embolism. Chest. 2013 Dec 1;144(6):1893-9. http://journal.publications.chestnet.org/article.aspx?articleid=1733328

2. McKeever T, Harrison TW, Hubbard R, Shaw D. Inhaled corticosteroids and the risk of pneumonia in people with asthma: a case-control study. Chest. 2013 Dec 1;144(6):1788-94. http://journal.publications.chestnet.org/article.aspx?articleid=1733331

3. Falagas ME, Avgeri SG, Matthaiou DK , et al. Short- versus long-duration antimicrobial treatment for exacerbations of chronic bronchitis: a meta-analysis. J Antimicrob Chemother . 2008 ; 62 ( 3 ): 442-450. http://jac.oxfordjournals.org/content/62/3/442.long

4. Dimopoulos G, Poulakou G, Pneumatikos IA, et al. Short- vs Long-Duration Antibiotic Regimens for Ventilator-Associated Pneumonia: A Systematic Review and Meta-analysis. Chest. 2013 Dec 1;144(6):1759-67. http://journal.publications.chestnet.org/article.aspx?articleid=1698747

5. Hedrick TL, McElearney ST, Smith RL, et al. Duration of antibiotic therapy for ventilator associated pneumonia caused by non-fermentative gram negative bacilli. Surg Infect (Larchmt). 2007; 8 (6): 589 – 597. http://online.liebertpub.com/doi/abs/10.1089/sur.2006.021

6. Darvish-Kazem S, Gandhi M, Marcucci M, et al. Perioperative management of antiplatelet therapy in patients with a coronary stent who need noncardiac surgery: a systematic review of clinical practice guidelines. Chest. 2013 Dec 1;144(6):1848-56. http://journal.publications.chestnet.org/article.aspx?articleid=1725196

7. Iakovou I, Schmidt T, Bonizzoni E, et al . Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents. JAMA. 2005; 293 (17): 2126 – 2130. http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.293.17.2126

 

 

 

 

 

Primecuts – This Week In The Journals

December 16, 2013

By Cilian White, MD

Peer reviewed

With the holiday season upon us, the streets are laden with trees waiting to be adorned, bunches of mistletoe to be hung for that special moment; and New Yorkers are wiping away the cobwebs from snow boots and thermal gear in preparation for the chill effect awaiting them as they step outside their homes. People adorn their homes with decorations, and enjoy delectable delights with loved ones. The NYU community continues to work harder than ever to provide care for those in times of illness, and those less fortunate than ourselves, especially at this time of year.

The chill effect not only pertains to this time of year, however. Therapeutic hypothermia is recommended in international resuscitation guidelines as a modality to reduce neurologic deficits after cardiac arrest. Two previous trials (1,2) had compared therapeutic hypothermia (to 32o and 34 o C) with standard therapy, the seminal results of which showed a significant improvement in neurologic function and survival. The NEJM presents a recent international, multicenter randomized clinical trial by Nielsen and colleagues investigating the benefits and harms of two temperature regimens (33o and 36o C) to assess whether or not previous reports were confounded by prevention of fever and poor thermal regulation as an effect on outcomes (3). Patients were randomly assigned to either the 33oC group (n=473), or 36oC group (n=466), with similar prerandomization characteristics. Temperature was managed with an intravascular cooling catheter in 24% of patients, and a surface cooling system in 76% of patients in both groups, with an intervention time of 36 hours. At the end of their trial, 50% of the 33oC patient group had died, compared to 48% in the 36oC group (HR with 33oC 1.06; 95% confidence interval (CI), 0.89 to 1.28; P = 0.51). At 180-day follow-up, 54% of the patients in the 33°C group had died or had poor neurologic function, as compared with 52% of patients in the 36°C group (risk ratio, 1.02; 95% CI, 0.88 to 1.16; P = 0.78). The researchers concluded that a therapeutic temperature of 33oC in unconscious survivors of out-of-hospital cardiac arrest did not confer a benefit over 36oC. A limitation of their study is that in all centers, intensive care staff members were aware of target temperature, potentially inducing bias; furthermore, the effects of sedation and neuromuscular blockade were not documented and may have significant impact on patient outcomes. One might subsequently hypothesize that maintenance of normothermia and fever prevention after cardiac arrest are equally effective, however this has yet to be evaluated in a randomized controlled trial.

Mistletoe, a well-known holiday season decoration under which couples share a special moment, is in its natural habitat (varietals Viscum album in Europe, and Phoradendron Serotinum in North America) a parasitic growth that can eventually kill its host. It may come as a surprise that mistletoe has another less apparent use – as a therapy for cancer; seemingly fitting to its effect in nature. Indeed, there are at least 30 different preparations available for this use. The Oncology section of the Lancet presents an interesting article (4) on extracts of Viscum Album as an adjunct anticancer therapy, prescribed almost uniquely in Europe. Mistletoe is thought to stimulate the immune system, help improve side effects of chemotherapy and radiotherapy, and improve quality of life. The actions of mistletoe pertain to biologically active molecules, such as mistletoe lectins, viscotoxins, flavonoids, and membrane lipids. Lectins and viscotoxins appear to be most attributable to a therapeutic role, inducing apoptosis and stimulating proliferation of neutrophils and natural killer cells. Many clinical studies of mistletoe effects exist; however the results are inconclusive in large part because of weak methodology, small sample sizes and failure to randomize. A Cochrane review in 2010 was unable to find conclusive research data to support clinical efficacy of mistletoe extract for use in cancer therapy (5). So an interesting concept, though perhaps it should remain as a decoration to kiss under, and not as an anticancer drug until further evidence becomes available.

Having stepped out of the cold and considered a kiss under the mistletoe, the smell of delicacy hits your nose – cinnamon, ham, duck, stuffing, roasted vegetables. Your eyes wander, soaking in the festive sights, and fall upon the dessert display, as you prepare for a holiday feast. Your blood pressure rises, and your doctor’s cautions of hypercholesterolemia are put to the back of your mind as you contemplate what is set out before you. The BMJ presents research by Shen and colleagues (6), who present a reanalysis of data from the Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial. This was a multinational, randomised, double blinded, placebo controlled trial of 9306 patients examining the effects of valsartan and nateglinide on conversion to type 2 diabetes mellitus and cardiovascular outcomes in patients with impaired glucose tolerance and other cardiovascular risk factors.

In this reanalysis of data, Shen and colleagues assessed number of patients who were initially not on beta blockade, diuretics, statins, or calcium channel blockers, and who subsequently commenced these medications during follow-up. Fasting blood glucose and HbA1c levels for these patients were reportedly similar compared to those in patients who never started on any of the four therapies. Of the 9306 participants enrolled, 915 (16.2%) of 5640 who were β blocker naïve at baseline started β blocker treatment, 1316 (20.7%) of 6346 who were diuretic naïve started diuretic treatment, 1353 (22.0%) of 6146 who were statin naïve started statin treatment, and 1171 (18.6%) of 6294 who were calcium channel blocker naïve started calcium channel blocker treatment. After adjustment for baseline and time varying confounders, Shen and colleagues deduced that diuretic and statin use were significantly associated with new onset diabetes. For β blockers, a non-significant difference in the development of new onset diabetes was observed. They conclude that in high risk people with impaired glucose tolerance, the use of diuretics and statins may be associated with an increased risk of new onset diabetes. While the study is large giving it power, the researchers note that their work was a reanalysis of a clinical trial that was not prospectively designed to examine the association between new onset diabetes and β blocker, statin, and diuretic use. They further add that biases due to the observational nature of treatment assignment were possible. In addition, no data on drug dosage or category were provided, limiting our deduction of dose-related outcome.

While enjoying your holiday season, you find that your ticklish cough that has continued for the past few weeks is just not going away, and have noticed a speck of blood not attributable to cranberry sauce. You decide to stop smoking in the new year as a resolution to yourself, but you are concerned. Screening for lung cancer has been a proposition for many years. Should you consider a screening CT? Recent results from the National Lung Screening Trial (NLST) (7), a randomized trial comparing screening of 53,452 people at high risk for lung cancer demonstrated a 20% relative reduction in lung cancer–specific mortality with low-dose computed tomography (LDCT) compared with screening using chest radiography (CXR). The trial notably found more cases of lung cancer in the LDCT group, though an article in JAMA Internal Medicine by Patz and colleagues (8) proposes that lesions found may indeed be indolent and clinically insignificant; suggesting that over-diagnosis may incur unnecessary treatment, morbidity/mortality, follow-up, cost, and anxiety for a patient with a disease that may otherwise have never been detected or become clinically significant. In this regard, Patz and colleagues used data from the NLST to provide an empirical estimate of the excess number of lung cancers reported in the LDCT arm of the NLST compared with the CXR arm. They propose a model to estimate the number of over-diagnoses relative to the number needed to screen to prevent one lung cancer death as the number of excess lung cancer cases in the LDCT arm of the NLST divided by the difference in lung cancer deaths in the LDCT and CXR arms of the NLST. Their findings report 18% of all lung cancers detected by LDCT in the NLST appeared to be indolent, and that over-diagnosis should be considered. Indeed, the researchers emphasize that if these individuals had not entered the NLST, they would not have received a lung cancer diagnosis or treatment for at least the next 5 years. They conclude that whereas the NLST demonstrated a relative mortality reduction with LDCT, the limitations of the screening process including the magnitude of over-diagnosis, should be considered when guidelines for mass screening programs are constructed.

 

Further reading:

1. The U.S. Food and Drug Administration approved sofosbuvir to treat chronic hepatitis C virus (HCV) infection. This is the first drug that has demonstrated safety and efficacy to treat certain types of HCV infection without the need for co-administration of interferon. Two studies (POSITRON, FUSION) made way for this treatment approval, reporting a profound decrease in circulating levels of HCV RNA, among both genotype 2 and 3 HCV-infected patients with sofosbuvir in combination with ribavirin.

Jacobson IM, Gordon SC, Kowdley KV, et al. Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options. N Engl J Med. 2013;368(20):1867-1877. http://www.nejm.org/doi/full/10.1056/NEJMoa1214854

 

2. A current article in Nature Medicine provides new insight into how metformin elicits its therapeutic effects, an area under scrutiny. A new study in mice shows that inhibitory phosphorylation of acetyl-coA carboxylases by the AMP-activated protein kinase (AMPK) is essential for the ability of metformin to improve insulin sensitivity and lower blood glucose in obesity.

Shaw RJ. Metformin trims fats to restore insulin sensitivity. Nature Medicine. 2013;19(12):1649-1654. http://www.nature.com/nm/journal/v19/n12/pdf/nm.3414.pdf

 

Dr. Cilian White is a 2nd year resident, Internal Medicine, at NYU Langone Medical Center

Peer reviewed by Brian Greet, Associate Editor, Clinical Correlations

Image courtesy of Wikimedia Commons


References

1. Moulaert VR, Verbunt JA, van Heugten CM, et al. Cognitive impairments in survivors of out-of-hospital cardiac arrest: a systematic review. Resuscitation. 2009;80:297-305. http://www.sciencedirect.com/science/article/pii/S0300957208007879#

 

2. Bernard SA, Gray TW, Buist MD, et al. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med. 2002;346:557-563.  http://www.nejm.org/doi/full/10.1056/NEJMoa003289

 

3. Nielsen N, Wetterslev J, Cronberg T, et al. Targeted Temperature Management at 33oC versus 36oC after Cardiac Arrest. N Engl J Med. 2013;369:2197-2206. http://www.nejm.org/doi/full/10.1056/NEJMoa1310519

 

4. de Giorio A, Stebbing J. Mistletoe: for cancer or just for Christmas? Lancet Oncol. 2013;14(13):1264-1265. http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70560-6/fulltext

 

5. Horneber M, Bueschel G, Huber R, et al. Mistletoe treatment in cancer patients. Cochrane Summaries. 2010. http://summaries.cochrane.org/CD003297/mistletoe-treatment-in-cancer-patients

 

6. Shen L, Shah BR, Reyes EM, et al. Role of diuretics, β blockers, and statins in increasing the risk of diabetes in patients with impaired glucose tolerance: reanalysis of data from the NAVIGATOR study. BMJ. 2013;347:f6745. http://www.bmj.com/content/347/bmj.f6745.pdf%2Bhtml

 

7.  Aberle DR, Adams AM, Berg CD, et al. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med.2011;365(5):395-409. http://www.nejm.org/doi/full/10.1056/NEJMoa1102873

 

8. Patz EF, Pinsky P, Gatsonis C, et al. Overdiagnosis in Low-Dose Computed Tomography Screening for Lung Cancer. 2013;173(22):E1-E6.  http://archinte.jamanetwork.com/article.aspx?articleid=1785197

 

 

 

Primecuts – This Week In The Journals

December 9, 2013

By Iulia Giuroiu, MD

Peer reviewed

As we mourn the death of Nelson Mandela and reflect upon his legacy, let us remember to embrace our differences as we strive toward well being for all. This week, the journals highlight the importance of paying attention to genetic risk factors unique to gender and ethnic backgrounds as we seek to provide optimal therapy for a variety of conditions.

This week’s first article challenges the assumption of gender equality in the use of drug-eluting stents (DES) (1). With a strong nod of support toward evidence-based practice, the Lancet looks at the safety and efficacy of DES placement in women, noting that initial trials on these devices were performed in men (1). Data on 11,557 female patients from 26 randomized trials involving DES conducted in the early 2000s were pooled, and results compared early generation DES (sirolimus- and paclitaxel-eluting) to newer-generation DES (everolimus-, zotarolimus-, biolimus-, and sirolimus-eluting) and to bare-metal stents (BMS). The composite primary safety endpoint of death or myocardial infarction occurred in 10.3% of the patients. Although the differences in deaths among the three groups were small, newer-generation DES were associated with significantly fewer rates of myocardial infarction, definite or probable stent thrombosis, and definite stent thrombosis. The primary efficacy endpoint of rate of target-lesion revascularization was also lowest in women receiving newer-generation DES. However, the authors point out that this was, after all, an observational study on a subgroup of patients, and that correct appraisal of the effects of DES in women would have to be carried out prospectively. Indeed, with gender known to confer different cardiovascular risk factors, prospective trials enrolling women and men in separate but parallel studies may prove most useful. This may pose challenges in recruiting sufficient numbers of patients to each trial but may ultimately prove the safest and most correct approach to study design.

Switching gears from cardiovascular to renal disease, NEJM looks at a combined report of two studies on the association between specific genetic variants and faster progression of chronic kidney disease in black versus white patients (2). In particular, these studies seek more robust data for the association between increased risk of HIV nephropathy, focal segmental glomerulosclerosis, chronic kidney disease due to hypertension, and non-diabetic end-stage renal disease and two genes: MYHN9, the gene encoding nonmuscle myosin heavy chain 9, and APOL1, the gene encoding apolipoprotein L1 whose two variants, G1 and G2 have been associated with resistance to deadly Trypanosoma brucei infections in patients of African origin.

The first of these studies, the African American Study of Kidney Disease and Hypertension (AASK) analyzed the composite primary outcome of doubling of the creatinine level/reduction in GFR by 50% and progression to end-stage renal disease in 693 patients who had initially been randomized to intensive versus standard blood pressure control (goal MAP ≤92 versus 102-107) with either ramipril, metoprolol, or amlodipine. Fifty-eight percent of the enrolled patients reached the composite outcome, with patients carrying two copies of the APOL1 risk variants proving twice as likely to attain both the composite outcome and end-stage renal disease alone. No difference in risk was noted between patients carrying only one copy of the risk variants as compared to the control group. Additionally, no significant difference was noted between patients with two copies of the high-risk MYH9 haplotype and patients who did not carry any risk alleles.

Subsequently, the second study involving APOL1 followed the rate of progression of chronic kidney disease in 2955 diabetic and non-diabetic white and black patients. The Chronic Renal Insufficiency Cohort (CRIC) study enrolled patients with and without the APOL1 high-risk variants. Primary outcome was the rate of decline in GFR and a composite of decline in GFR by 50% and end-stage renal disease. With the results stratified by diabetes status, the fastest decline in renal function and most likely progression to the composite outcome were both highest in high-risk black patients with two copies of the APOL1 risk variant, followed by low-risk carriers of an APOL1 variant, followed by white patients.

Although exact causal relationships between the APOL1 gene variants and progressive renal dysfunction have yet to be uncovered, both AASK and CRIC raise strong arguments for further genetic analysis to identify a specific causal link, as well as for new trials to determine optimal therapeutic strategies for slowing down or even preventing progression of renal disease among high-risk patients.

Finally in the realm of risk stratification, the Annals present a cohort study that proposes a more accurate risk predictor for the development of atrial fibrillation (AF). The current model for calculating a patient’s 10-year risk for developing AF is based on the Framingham Heart Study and factors in age, BMI, systolic blood pressure, presence or absence of treatment for hypertension, PR interval length, age at which a significant cardiac murmur developed, and age of heart failure (4). A follow-up study also included race as a variable, particularly considering that black patients have been shown to have a somewhat lower risk of AF than white patients (5). Noting that premature atrial contractions (PACs) can trigger AF, Dewland and colleagues conducted a prospective, community-based cohort study to look for an association between PACs and AF (3). 1429 patients underwent 24-hour Holter monitoring at enrollment, and ECGs were obtained annually; diagnosis codes on discharge from any hospital admissions were also reviewed for AF. At median follow-up 13 years after enrollment, patients who had developed AF had had a significantly higher baseline frequency of PACs. Hourly PAC counts of 32 or higher showed greater than 90% specificity for 15-year AF risk. Additionally, PAC counts further refined risk stratification within the Framingham risk model. This study may pave the way for investigations into potential benefits of PAC ablation in preventing the negative sequelae of AF.

Further reading:

1. Nature Medicine proposes a pathway for metformin’s mechanism of action: In mice, metformin activates AMP-activated protein kinase, which leads to downstream inhibition of the conversion of acetyl-CoA to malonyl-CoA. Inhibition of this early step in fatty acid synthesis prevents fatty acid accumulation in the liver, which in turn prevents insulin resistance in hepatocytes. Understanding the role of metformin at the molecular level not only sheds light on the effectiveness of a popular drug in the treatment of diabetes but also helps build a rationale for metformin’s use in diseases that share these molecular pathways.

Fullerton MD, Galic S, Marcinko K, et al. Single phosphorylation sites in Acc1 and Acc2 regulate lipid homeostasis and the insulin-sensitizing effects of metformin. Nat Med. 2013; 19:1649-1654. http://www.nature.com.ezproxy.med.nyu.edu/nm/journal/v19/n12/full/nm.3372.html

Shaw, RJ. Metformin trims fats to restore insulin sensitivity. Nat Med. 2013;19:1570-1572. http://www.nature.com.ezproxy.med.nyu.edu/nm/journal/v19/n12/full/nm.3414.html

2. A meta-analysis in JAMA Internal Medicine reveals a decrease in long-term mortality and myocardial infarctions in patients with multivessel coronary disease undergoing CABG as compared to PCI, taking us a step closer to determining the optimal treatment of this group of patients. The increased stroke risk associated with CABG was mitigated by decreased overall mortality, and the authors argue that these results hold true for diabetics as well. Since the study is limited by its retrospective nature, the availability of trial-level data only and the resultant lack of subgroup analysis, and the lack of inclusion of trials with newer-generation DES, perhaps a patient-level analysis of data from existing trials or even new prospective trials may help support or refute this study that supports a major shift in practice.

Sipahi I, Akay MH, Dagdelen S, et al. Coronary Artery Bypass Grafting vs Percutaneous Coronary Intervention and Long-term Mortality and Morbidity in Multivessel Disease: Meta-analysis of Randomized Clinical Trials of the Arterial Grafting and Stenting Era. JAMA Intern Med. Epub: December 2, 2013. doi:10.1001/jamainternmed.2013.12844 http://archinte.jamanetwork.com/article.aspx?articleid=1783046

3. As reported by the Annals of Internal Medicine, obese patients who are metabolically healthy remain at risk for long-term negative outcomes such as increased mortality and cardiovascular complications. However, normal-weight metabolically unhealthy individuals also face increased risks of mortality and cardiovascular events. Thus, we should continue to promote weight loss in our obese patients and to aggressively treat metabolically unhealthy patients in any BMI range. Better yet, promoting healthy lifestyles to prevent our patients from entering either of these categories may ultimately prove the least confounding.

Kramer CK, Zinman B, Retnakaran R. Are Metabolically Healthy Overweight and Obesity Benign Conditions?: A Systematic Review and Meta-analysis. Ann Intern Med. 2013;159:758-769. http://annals.org/article.aspx?articleid=1784291

Dr. Ilulia Giuroiu is a 3rd year resident, Internal Medicine, at NYU Langone Medical Center

Peer reviewed by Brian Greet, Associate Editor, Clinical Correlations

Image courtesy of Wikimedia Commons

References

1. Stefanini GG, Baber U, Windecker S, et al. Safety and efficacy of drug-eluting stents in women: a patient-level pooled analysis of randomized trials. Lancet. 2013;382:1879-1888. http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(13)61782-1/fulltext

2. Parsa A, Kao L, Xie D, et al. APOL1 Risk Variants, Race, and Progression of Chronic Kidney Disease. N Engl J Med. 2013;369:2183-2196. http://www.nejm.org/doi/full/10.1056/NEJMoa1310345#t=article

3. Dewland TA, Vittinghoff E, Mandyam MC, et al. Atrial Ectopy as a Predictor of Incident Atrial Fibrillation: A Cohort Study. Ann Intern Med. 2013;159:721-728. http://annals.org.ezproxy.med.nyu.edu/article.aspx?articleid=1784287

4. Schnabel RB, Sullivan LM, Levy D, et al. Development of a risk score for atrial fibrillation (Framingham Heart Study): a community-based cohort study. Lancet. 2009;373:739-745. http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60443-8/fulltext

5. Chamberlain AM, Agarwal SK, Folsom AR, et al. A Clinical Risk Score for Atrial Fibrillation in a Biracial Prospective Cohort (From the Atherosclerosis Risk in Communities [ARIC] Study). Am J Cardiol. 2011;107:85-91. http://www.sciencedirect.com/science/article/pii/S0002914910017327

 

 

Primecuts – This Week In The Journals

December 3, 2013

By Matthew Lee, MD

Peer Reviewed

Thanksgiving has traditionally been characterized by turkey-centric meals and Black Friday madness, but these phenomena were joined this year by both NCAA football’s rivalry week and Thanksgivukkah (the alignment of Thanksgiving and first day of Hanukkah). While people took time off to celebrate the holiday festivities, the medical journal world continued to turn, bringing us to this week’s articles.

Our first article by Mulder et al. [1] looks at glucose management in patients admitted for acute coronary syndrome (ACS). Prior studies found that elevated glucose levels at admission were associated with an increased risk of mortality in both diabetic and non-diabetic patients [2]. Follow-up studies on glucose control and its effect on mortality and morbidity have revealed conflicting results. In this open-label randomized study, Mulder et al. evaluated whether glucose control could limit infarct size. The primary outcome of the study was median troponin level after 72 hours with secondary outcomes consisting of the area under the curve of CK-MB levels, perfusion imaging at six weeks, and a composite of all-cause death and second nonfatal myocardial infarction (MI). Patients admitted with ACS were randomized to either “intensive” (goal FSG < 140 through use of IV insulin) or “conventional” (goal < 288) groups.

No statistical difference in the primary and most secondary endpoints was found 72 hours after admission, with the authors concluding that intensive glucose control does not limit infarct size. There were significant potential flaws in the methodology of the study including delays in insulin initiation (often hours post-intervention) and the exclusion of insulin-dependent diabetics. In addition, the authors noted that there was an increase in the composite end-point of death or second spontaneous MI in those receiving intensive glucose control, yet conclusions are difficult to draw from this secondary outcome.

Continuing with the diabetes theme, a new study by Huang et al. [3] investigated the effect of new onset of diabetes in chronic hepatitis B patients and the risk of progression to cirrhosis. This Taiwanese cohort study followed roughly 8000 non-cirrhotic, hepatitis B patients over a 9-year period. Outcomes were compared between those receiving a new diagnosis of diabetes (n=351) versus non-diabetics (n=7886). Noteworthy exclusion criteria were any previous diagnoses of varices, hepatitis C, primary biliary cirrhosis, or alcoholic liver disease in order to minimize cirrhotic risk factors. At the end of the study, the diabetic cohort had both an elevated risk of new onset cirrhosis (relative risk [RR] 3.43, 95% CI, 2.62-4.49; absolute risk increase of 8.2%) and hepatocellular carcinoma (absloute risk increase of 3.5%) when compared to the non-diabetic cohort. In addition, diabetic patients were found to be at higher risk for developing decompensated cirrhosis (RR 4.11, 95% CI, 2.95-5.70). When controlling for clinical characteristics (including age, co-morbidities, and hepatitis B treatment), the study also found diabetes to be an independent predictor for cirrhosis development (hazard ratio 1.792, 95% CI, 1.192-2.695). These findings provide initial evidence that the development of diabetes in hepatitis B patients can accelerate the progression to cirrhosis. This study highlights an important preventative measure already in place: diabetic screening in hepatitis B patients, which stands in juxtaposition to the CDC recommendation for all diabetics under 60 to receive the hepatitis B vaccine [4]. Further investigation into whether tight glucose control could change disease progression of hepatitis B is also warranted.

Lastly, Starling et al. [5] reported on an increasing rate of left ventricular assist device (LVAD) thrombosis observed from March 2011 to January 2013. Initial post-approval studies prior to 2011 had reported an LVAD thrombosis rate up to 4% [6]. However, single-center reports of higher incidence rates led to this multi-center, observational study. The primary end-point was confirmed pump thrombosis (defined as thrombus found on the blood-contacting surfaces of the HeartMate II, its inflow cannula, or its outflow conduit at pump replacement, urgent transplantation, or autopsy) with secondary end-points including clinically suspected thrombosis, LDH levels (indicating hemolysis), and outcomes of thrombosis management. The study found that the incidence of thrombosis 3 months post-implantation increased from 2.2% (95% CI, 1.5-3.4) in March 2011 to 8.4% (95% CI, 5.0-13.9) in January 2013. There was also a notable decrease in time from implantation to thrombosis of 18.6 months (95% CI, 0.5-52.7) to 2.7 months (95% CI, 0.0-18.6) over the same time period. LDH levels were notable for a near 3-fold increase over 6 weeks prior to thrombosis. Strikingly, patients with thrombosis who were not treated with urgent heart transplantation or device replacement had a mortality of 48.2% (95% CI, 31.6-65.2) at 6 months. The reason behind the increased thrombosis rate remains unknown, but is likely multifactorial in nature. It remains unclear how management decisions will be impacted in light of this new information.

Other notable articles include:

A study from JAMA looked at the relationship between physician’s diagnostic accuracy and confidence. Physicians were presented with “easy” and “difficult” clinical cases and then asked about their confidence level on a scale from 0-10. Despite maintaining confidence levels of 6-7/10, only 5.8% of physicians were able to correctly diagnose the “difficult” cases. This discordance between correct diagnosis and confidence level highlights the need to maintain an ability to “step back” and re-evaluate, particularly in challenging cases.

Meyer AN, Payne VL, Meeks DW, et al. Physicians’ diagnostic accuracy, confidence, and resource requests: A vignette study. JAMA Intern Med. 2013;173(21):1952-1959. http://archinte.jamanetwork.com/article.aspx?articleid=1731967

An article in the NEJM presented data from a large, pharmaceutical-funded, randomized, double blind non-inferiority trial comparing low-dose (30 mg daily) or high-dose (60 mg daily) edoxaban (a direct Xa inhibitor; trade name Lixiana) to warfarin. Both low and high-dose edoxaban were found to be non-inferior in regards to primary end points (stroke or systemic embolic events) with edoxaban also found to have lower major adverse bleeding events. The study presented supportive data for yet another oral anti-coagulant and highlighted the potential for a decrease in bleeding outcomes with this novel agent.

Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013 Nov 28;369(22):2093-2104. http://www.nejm.org/doi/full/10.1056/NEJMoa1310907

Dr. Matthew Lee is a second 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. Mulder M, Umans VA, Cornel JH, et al. Intensive glucose regulation in hyperglycemic acute coronary syndrome. JAMA Intern Med. 2013;173(20):1896-1904. http://archinte.jamanetwork.com/article.aspx?articleid=1735896

2. Stranders I, Diamant M, van Gelder RE, et al. Admission blood glucose level as risk indicator of death after myocardial infarction in patients with and without diabetes mellitus. Arch Intern Med. 2004;164(9):982-988. http://archinte.jamanetwork.com/article.aspx?articleid=216997

3.Huang YW, Wang TC, Lin SC, et al. Increased risk of cirrhosis and its decompensation in chronic hepatitis B patients with newly diagnosed diabetes: A nationwide cohort study. Clin Infect Dis. 2013;57(12):1695-1702. http://cid.oxfordjournals.org/content/57/12/1695.abstract

4. Centers for Disease Control and Prevention. Use of hepatitis B vaccination for adults with diabetes mellitus: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR. 2011;60(50):1709-1711. http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6050a4.htm

5. Starling RC, Moazami N, Silvestry SC, et al. Unexpected abrupt increase in left ventricular assist device thrombosis. N Engl J Med. Nov 27 2013; e-pub ahead of print. http://www.nejm.org/doi/full/10.1056/NEJMoa1313385

6. Miller LW, Pagani FD, Russell SD,et al. Use of a continuous-flow device in patients awaiting heart transplantation. N Engl J Med 2007;357:885-896. http://www.nejm.org/doi/full/10.1056/NEJMoa067758#t=articleResults