Primecuts – This Week In The Journals

September 12, 2016

9-11_Memorial_NamesBy Katherine Lawrence, MD

Peer Reviewed

Yesterday marked the 15th anniversary of September 11, 2001. Fifteen years later, emotions are still strong; it was a day of memorials and memories, a celebration of those who gave their lives and reminder of the challenges that remain.

One of the many powerful legacies of 9/11 has been the chronicling of its health impacts. Both the city of New York and the federal government (including the Center for Disease Control and Prevention and the National Institute for Occupational Safety and Health) have established and maintained programs that collect data on 9/11 first responders and civilians, as well as providing medical care to those populations. The NYU School of Medicine is one of seven centers established by the James Zadroga 9/11 Health and Compensation Act of 2010. To date, 74,968 people have enrolled in one of these programs.

Fifteen years later, we are still discovering the health consequences of 9/11. On Saturday, New York Magazine wrote an article summarizing some of the things we have learned so far. Among the illnesses that the 9/11 fallout-exposed are at increased for are asthma, GERD, PTSD, and sarcoidosis. Cancer risks also appear to be increased, including prostate, thyroid, and breast, although the link is not definitive.

Just as important as a memorial for those who gave their lives, 9/11 is a tribute to those who served, survived, and are continually impacted by the events of that day. It is also a reminder to us in the medical community of the importance of occupational, environmental, and social determinants of health for our patients.

Here are reviews of other articles in medicine and health that made headlines this week:

Association Between MRI Exposure During Pregnancy and Fetal and Childhood Outcomes

Optimal imaging of pregnant women is a topic of continued discussion in the medical community. Magnetic resonance imaging during pregnancy is generally thought to be safe for the fetus, especially in the second or third trimester. Concerns about exposures in the first trimester, or exposures to gadolinium at any time during pregnancy, however, have resulted in recommendations to avoid these particular modalities, despite limited high-quality data regarding safety to the fetus.

A study in JAMA looked at the association between MRI exposure during pregnancy and fetal and childhood outcomes. A retrospective cohort study using universal health care databases in the province of Ontario, Canada was conducted at the Institute for Clinical Evaluative Sciences (ICES). Researchers identified all births of more than 20 weeks, from 2003-2015, to evaluate Magnetic resonance imaging exposure in the first trimester of pregnancy, or gadolinium MRI exposure at any time in pregnancy. Study outcomes for the first-trimester MRI cohort included stillbirth after 20 weeks’ gestation or neonatal death before 28 days after birth, congenital anomalies, neoplasm, vision loss, and hearing loss. Study outcomes for the gadolinium-enhanced MRI during pregnancy cohort included any diagnosed rheumatological, inflammatory, or infiltrative skin condition.

Among the first-trimester cohort, maternal MRI in the first trimester was not associated with a higher risk of stillbirth or neonatal death (adjusted RR of 1.68 (95%CI, 0.97 to 2.90)), congenital anomalies (HR of 1.16 (95% CI, 0.96 to 1.40), neoplasm, or hearing loss. The risk of vision loss was only seen in a subgroup analysis of MRI exposure at 5 to 10weeks’ gestation HR of 2.28(95%CI, 1.09-4.77). Among the gadolinium-exposed group, the study found gadolinium-enhanced MRI was associated increased risk of any rheumatological, inflammatory or infiltrative skin condition up to age 4 years (adjusted HR of 1.36 (95% CI, 1.09 to 1.69), and an almost four-fold risk of stillbirth or neonatal death (Adjusted RR 3.70 (95% CI, 1.55-8.85)), when compared to offspring of unexposed women.

The strengths of the study came from the large sample size (N = 1 420 188 in the first trimester cohort and N =1 418 848 in the gadolinium cohort) and the robustness of the data, having been derived from a centralized national database. Due to the relatively small numbers of exposed participants, however, many of the analyses conducted were underpowered to assess less common outcomes, resulting in less thorough evaluation of rare malformations. Additionally, follow-up was limited to four years, and therefore may not have captured later-onset disease in participants. Ultimately, this study provides an important contribution to peri-natal care, reinforcing that avoidance of gadolinium-enhanced MRIs in pregnancy should be recommended, and informing risk-benefit discussions with pregnant patients regarding possible congenital effects of imaging. 

CPAP for Prevention of Cardiovascular Events in Obstructive Sleep Apnea 

Obstructive sleep apnea (OSA) affects 40-60% of Americans with cardiovascular disease, and is associated with adverse cardiovascular events, including hypertension and stroke. Continuous positive airway pressure (CPAP) is a commonly prescribed intervention for individuals who suffer from sleep apnea. In addition to improving breathing, CPAP has also been shown to lower systolic blood pressure, improve endothelial function, and increase insulin sensitivity, thereby having potential additional benefits for patients with cardiovascular disease.

A recent study in the NEJM evaluated the impact of continuous positive airway pressure (CPAP) on major cardiovascular events in patients with known cardiovascular disease and sleep apnea. The SAVE study was an international, multicenter, randomized, parallel-group, open-label trial, conducted under the supervision of The Adelaide Institute for Sleep Health of Flinders University of South Australia. The National Health and Medical Research Council of Australia and Philips Respironics funded the project, with Philips donating the CPAP equipment.

The study looked specifically at participants between 45 and 75 years, who held a diagnosis of coronary artery disease or cerebrovascular disease, as well as a diagnosis of moderate-to-severe obstructive sleep apnea (defined as an oxygen desaturation index >=12). After a 1-week sham CPAP trial, participants were randomly assigned to receive CPAP treatment plus usual care (CPAP group) or usual care alone (usual-care group). Anthropometric measurements were obtained at specific intervals, including blood pressure and heart rate, EKGs, as well as questionnaire data on OSA symptoms, health behaviors, and quality of life. The primary composite end point was death from cardiovascular causes, myocardial infarction, stroke, or hospitalization for unstable angina, heart failure, or transient ischemic attack. Secondary end points included other cardiovascular outcomes, health-related quality of life, snoring symptoms, daytime sleepiness, and mood.

In a blow to CPAP manufacturers, the study determined therapy with CPAP as compared with usual care did not prevent cardiovascular events in patients with moderate-to-severe obstructive sleep apnea and established cardiovascular disease. Results failed to show a significant difference in the primary outcome of death or hospitalization due to cardiovascular events between the experimental and control groups (hazard ratio with CPAP, 1.10; 95% confidence interval, 0.91 to 1.32; P = 0.34). The study did show, whoever, that CPAP decreased the mean apnea-hypopnea index (from 29.0 events per hour at baseline to 3.7 events per hour during follow-up), significantly reduced snoring and daytime sleepiness, and improved health-related quality of life and mood.

The results of this study are consistent with similar research in the area of CPAP and cardiovascular disease, which has shown no difference in outcomes. Limitations to the study included challenges in recruitment (5844 meeting eligibility criteria, 2687 were included in primary analysis and an additional 147 were lost to follow up). As is common in CPAP interventions, researchers also recognized substantial variation in adherence to the CPAP equipment. Finally, although the outcomes were not supportive of CPAP as a mechanism for improving cardiovascular events, potential bias remains in the funding of the project.

Safety and Effectiveness of Consumer Antiseptics; Topical Antimicrobial Drug Products for Over-the-Counter Human Use

The FDA has issued a final rule on safety and effectiveness of consumer antiseptic products, banning 19 chemicals found in these products, including triclosan and triclocarban, from the US market. The FDA is issuing this final rule after considering the recommendations of the Nonprescription Drugs Advisory Committee (NDAC), and evaluating the data available on over-the-counter (OTC) consumer antiseptic wash products. This rule is an update of the consumer antiseptic wash proposed rule published in 2013 (known as ‘the 2013 Consumer Wash Proposed Rule’) and amends a 1994 rule for OTC antiseptic drug products.

‘Consumer antiseptic washes’ include a variety of personal care products, such as antibacterial soaps, hand washes, and antibacterial body washes, which are meant to be used as part of a washing-with-water routine. In the 2013 legislation, the FDA determined that the benefits of consumer anti-septic wash products (including hand washes and body washes) outweighed potential risks; these products were subsequently approved and brought to market as a variety of ‘anti-bacterial’ soaps, washes, and other goods. New information, however, has revealed that the costs of these products may actually outweigh the benefits. In its evaluation of the effectiveness of anti-bacterial products, the FDA found “insufficient evidence to demonstrate that there is any additional benefit from the use of these [ingredients] compared to non-antibacterial soap and water.” The organization also determined that there is insufficient data “to establish the safety of long-term, daily repeated exposure to these active ingredients used in consumer wash products”. A cost-benefit analysis of the new ruling estimated a total annualized cost of $23.6-27.6 million to reduce population exposure to antiseptic ingredients by roughly 2.2 million pound each year.

Importantly, the FDA ruling applies only to consumer antiseptics. It does not cover health care antiseptics or antiseptics identified as “first aid antiseptics”. It also does not include consumer antiseptic ‘rubs’ (products meant to be used without washing off, like hand sanitizer gel or spray) or antiseptics used by the food industry. Also, the FDA has deferred further rulemaking on three specific active ingredients used in these products, “to allow for the development and submission of new safety and effectiveness data”. The ingredients are benzalkonium chloride, benzethonium chloride, and chloroxylenol. More information is needed to determine the impact of these chemicals.

The rule becomes effective in September 2017, so it may be a while before we see the full impact of the decision reach the shelves.


In the wake of scandal involving surgeon Paolo Macchiarini, the Swedish government has fired the entire board of the prestigious Karolinska Institute, for their involvement in falsifying medical research on stem cell transplantation and endangering the lives of patients: 

The CDC released a report at the beginning of this month documenting national estimates of marijuana use in the United States, from data collected by the National Survey on Drug Use and Health (NSDUH). The report suggests that there are roughly 7,000 new users every day: 

Last week, Mylan, the maker of the EpiPen auto-injector, announced a price-hike on their product right before the back to school rush: $600 for two pens, representing a 600% increase since the company bought the rights to the product in 2007. This has a resulted in public outrage, a media frenzy, and some important conversations on the state of our pharmaceutical markets: 

Dr. Katherine Lawrence is a 1st year resident at NYU Langone Medical Center

Peer reviewed by Neha Jindal, MD, associate editor, Clinical Correlations

Image courtesy of Wikimedia Commons


Brackbill R et al. Ten-year cancer incidence in rescue/recovery workers and civilians exposed to the September 11, 2001 terrorist attacks on the World Trade Center. Am J Ind Med. 2016 Sep;59(9):709-21. doi: 10.1002/ajim.22638.

Icitovic N et al. The association between body mass index and gastroesophageal reflux disease in the World Trade Center Health Program General Responder Cohort. Am J Ind Med. 2016 Sep;59(9):761-6. doi: 10.1002/ajim.22637.

Brackbill R et al. Asthma and Posttraumatic Stress Symptoms 5 to 6 Years Following Exposure to the World Trade Center Terrorist Attack. JAMA. 2009;302(5):502-516. doi:10.1001/jama.2009.1121.

NYU World Trade Center Program. Accessed 9/11/16.

FDA. Safety and Effectiveness of Consumer Antiseptics; Topical Antimicrobial Drug Products for Over-the-Counter Human Use. Accessed 9/11/16.

Ray J et al. Association Between MRI Exposure During Pregnancy and Fetal and Childhood Outcomes. JAMA. 2016;316(9):952-961. doi:10.1001/jama.2016.12126

McEvoy D et al. CPAP for Prevention of Cardiovascular Events in Obstructive Sleep Apnea. N Engl J Med 2016;375:919-31.

Primecuts – This Week In the Journals

August 30, 2016

zikaBy Nancyanne Schmidt, MD

Peer Reviewed

As we enter the final weeks of summer, the peril posed by the tiny mosquito continues to grow to shark-sized proportions. The FDA now recommends that all blood donations in the U.S. be screened for the Zika virus, after the agency had earlier advised only testing in areas with an active outbreak [1]. The FDA is recommending blood facilities in eleven states, including New York, to begin testing for Zika in the next four weeks.

On the other side of the Atlantic, many Europeans are enjoying the August holiday on the beach – but not without some controversy. On Friday, France’s highest administrative court overturned the ban on “burkinis” in the town of Villeneuve-Loubet [2]. Burkinis are full body swimwear worn by some Muslim women. The ruling made clear that such a ban violated civil liberties, including freedom of movement and religious freedom.

Meanwhile in the U.S., Colin Kaepernick became the most recent celebrity to take a stand for civil rights. The San Francisco 49ers quarterback became the latest in a string of high profile athletes who have used their platform to speak out about racism, civil rights issues and gun violence [3]. Kaepernick refused to stand during the national anthem before a game on Friday, protesting the treatment of racial minorities in the U.S.

From the latest and breaking news from around the world, we now look at the journal articles that have made headlines this week:

70-Gene Signature as an Aid to Treatment Decisions in Early-Stage Breast Cancer

Breast cancer is the most frequently diagnosed cancer in women and the leading cause of cancer death in women as well. Deciding to treat patients with adjuvant chemotherapy is based on tumor grade, size, nodal involvement, hormonal receptor status and individual characteristics such as age and performance status. However, since treatment decision algorithms often do not take into account individual genetic characteristics of tumors, it is reasonable to assume that a substantial number of patients with breast cancer may be receiving adjuvant chemotherapy unnecessarily. Using gene expression studies to analyze the unique genetic characteristics of breast tumors may be useful in deciding whether adjuvant chemotherapy is an appropriate treatment for each patient.

A study published this week in the New England Journal of Medicine used one such test, the 70-gene signature Mamma-Print, in addition to standard clinico-pathological data to select patients who would specifically benefit from adjuvant chemotherapy [4]. This international, prospective, randomized, phase 3 study examined five-year outcomes among 1550 breast cancer patients with high-risk clinical features but a low-risk gene-expression profile. Of these patients with discordant risk group analyses, 749 were assigned to receive chemotherapy, while 748 did not receive adjuvant chemotherapy. The aim was to assess whether patients with high-risk clinical features but a low-risk gene-expression profile could achieve the primary endpoint of 92% survival at five years. The five-year survival without distant metastasis was 94.7% (95% CI, 92.5 – 96.2%), which established noninferiority.

In the discordant group that did receive chemotherapy, the five year survival rate without distant metastasis was 1.5% higher in comparison with patients who did not receive adjuvant chemotherapy — 95.9% vs 94.4%. The study was not powered to assess the statistical significance of these differences but the magnitude of chemotherapy benefit appears modest when considering its cost, inconvenience and associated risks.

This study proves that it is possible to identify patients who may not benefit from adjuvant chemotherapy, although how patients and clinicians interpret the results of genetic tests in addition to clinical risk prognosticators will remain highly individualized.

Association of Integrated Team-Based Care With Health Care Quality, Utilization, and Cost

The benefits of patient care in team-based settings that combine mental health and primary care teams have been praised, but additional evidence of its utility in a large healthcare delivery system is still needed.

In a study published this week in The Journal of the American Medical Association, researchers sought to evaluate the outcomes of receiving care in integrated team-based practices vs traditional management practices [5]. This retrospective, longitudinal, cohort study assessed quality, hospital utilization and cost outcomes associated with receipt of primary care in team based practices. Since the year 2000, Intermountain Healthcare, a healthcare delivery system based in Utah and Idaho, has incorporated the use of physical and mental health teams in family medicine, pediatric and internal medicine primary care clinics. 113,452 unique adult patients from 113 Intermountain Medical group primary care practices were studied from January 2010 to December 2013, and these patients treated via Intermountain Healthcare team based care (TBC) were compared with those treated in traditional practices (TPM). Patients treated in the team based care model had higher rates of adherence to a diabetes care plan (24.6% for TBC vs 19.5% for TPM; odds ratio [OR] 1.26 [95%CI, 1.11 to 1.42]), active depression screening (46.1% for TBC vs 24.1% for TPM; OR 1.91 [95% CI, 1.75 to 2.08]), and documentation of self-care plans (48.4% for TBC vs 8.7% for TPM; OR 5.59 [95% CI, 4.27 to 7.33]). Of note, the TBC group had a lower proportion of patients with controlled hypertension (defined as <140/90 mmHg) – 85.0% for TBC vs 97.7% for TPM (OR 0.87 [95%CI, 0.80 to 0.95]). Rates of healthcare utilization were lower for patients in the TBC group including average number of emergency department visits (18.1 for TBC vs 23.5 for TPM; incidence rate ratio [IRR] 0.77 [95%CI, 0.74 to 0.80]), and average number of hospital admissions (9.5 for TBC vs 10.6 for TPM; IRR 0.89 [95%CI, 0.85 to 0.94]).

This study clearly demonstrates that in a team based care setting there can be improved quality of care for patients with depression and diabetes as well as reductions in some measures of acute care utilization. There are several drawbacks to this study, including but not limited to, the fact that Intermountain healthcare is a fully integrated delivery system, so direct translation of these results may be limited in settings without a similar support infrastructure.

A Placebo-Controlled Trial of Obeticholic Acid in Primary Biliary Cholangitis

Primary biliary cholangitis is characterized by T-lymphocyte mediated attack on interlobular epithelial bile duct cells leading to their destruction. The resultant cholestasis can lead to eventual cirrhosis, end-stage liver disease and death. Treatment with ursodeoxycholic acid delays progression to end stage liver disease as well as time to liver transplantation, however there is an unmet need for additional therapy options in PBC patients with persistent elevated alkaline phosphatase levels despite ursodiol treatment, as well as patients unable to tolerate treatment. Obeticholic acid (OCA), a farnesoid X receptor ligand agonist, impairs bile acid synthesis and stimulates choleresis, presenting a viable alternative for PBC patients [6]. In prior placebo controlled trials, obeticholic acid resulted in significantly greater decreases in alkaline phosphatase and bilirubin compared to placebo, but also demonstrated dose-related increases in the incidence and severity of pruritus [7].

A study published in The New England Journal of Medicine sought to assess the longer-term efficacy, safety, and adverse-event profile of obeticholic acid in patients with primary biliary cholangitis who were receiving daily doses of 5mg or 10mg [8]. In this double-blind, placebo- controlled, parallel-group, 12-month phase 3 trial, 216 patients (91% women, 94% white) were assigned to either receive placebo (N=73), obeticholic acid 5mg with an increase to 10mg after six months (N=70), or obeticholic acid 10mg (N=73), all of which were added to standard of care ursodiol 13-15mg/kg. The primary endpoints were an alkaline phosphatase level less than 1.67 times the upper limit of the normal range with a reduction of at least 15% from baseline, and a total bilirubin level at or below the upper limit of the normal range at 12 months. 46% of patients in the 5–10-mg group and 47% of patients in the 10-mg group achieved these endpoints compared to just 10% of those in the placebo group (P<0.001 for both comparisons). These effects were sustained for two years. Non-invasive measures of liver fibrosis, elastography and enhanced liver fibrosis score did not differ between either treatment group and the placebo group.  Pruritus was the most common adverse event across all groups (56% of patients in the 5–10-mg group and 68% of those in the 10-mg group vs. 38% in the placebo group).

This study demonstrates that treatment with obeticholic acid results in improvement in biochemical markers of disease in patients with inadequate response to or inability to tolerate ursodiol. Since this study examined patients for two years, it is unclear if obeticholic acid improve outcomes such as survival. This study cohort is part of a multiyear study to assess the effects of obeticholic acid on clinical outcomes in patients with primary biliary cholangitis who have more advanced liver disease.

Nonrandomized Intervention Study of Naloxone Coprescription for Primary Care Patients Receiving Long-Term Opioid Therapy for Pain

The United States is in the midst of an opioid overdose epidemic, with the death rate increasing from 1.4 per 100,000 adults in 1999 to 5.4 per 100,000 adults in 2011 [9]. Supplying those likely to experience or witness an overdose with naloxone has been associated with reductions in opioid overdose mortality [10]. However, literature to support prescription of naloxone in primary care settings is limited to anecdotes and early descriptive analyses.

A study published in the Annals of Internal Medicine aimed to better understand the feasibility of prescribing naloxone for patients already receiving opioid medications [11]. In this 2-year, nonrandomized intervention study conducted at six primary care clinics in San Francisco, 1985 adults receiving long-term opioid therapy were identified as candidates to receive naloxone. Naloxone was prescribed to 759 patients, or 38.2% of eligible clinic patients. Patients receiving higher opioid doses were more likely to be prescribed naloxone (adjusted odds ratio 1.73 [CI, 1.57 to 1.92]; P<0.001) as were those patients who were seen in the county Emergency Department for an opioid-related visit in the 12 preceding months (adjusted odds ratio 2.54 [CI, 1.54 to 4.18]; P<0.001). In the six months after receipt of the prescription, patients who received naloxone had 47% fewer opioid related ED visits per month (IRR, 0.53 [CI, 0.34 to 0.83]; P = 0.005) and a 63% reduction after 1 year (IRR, 0.37 [CI, 0.22 to 0.64]; P < 0.001) compared with those who did not receive a prescription. Limitations of this study include the lack of data to confirm that patients filled their naloxone prescriptions. It is also possible that patients received care outside of the safety net system. Lastly, causality cannot be inferred from this observational study.

This study demonstrated that when clinicians are properly advised, naloxone can be co-prescribed to primary care patients receiving opioids for pain with the ancillary benefit of reducing opioid related adverse events.


In a randomized trial, researchers found that MRI guided thalotomy improved hand tremor scores in patients with essential tremor [12]. This study provided the basis for the recent FDA approval of the first focused ultrasound device (ExAblate Neuro, InSightec) to treat essential tremor.

A retrospective study of men with prostate cancer showed that adding radiation to androgen-deprivation therapy improved survival [13].

The largest randomized trial to date comparing drug eluting stents to bare metal stents found similar outcomes with each stent at 6 years[14]. Drug eluting stents had lower rates of restenosis and thrombosis.

Dr. Nancyanne Schmidt is a 1st-year resident at NYU Langone Medical Center.

Peer reviewed by Dr. Amar Parikh, 3rd year internal medicine resident at NYU Langone Medical Center

Image courtesy of


  1. St. Louis Catherine. All Donated Blood in U.S. Should Be Tested for Zika, F.D.A. Says. NY Times [New York] 26Aug16.
  2. Breeden, Aurelien and Blaise, Lilia. Court Overturns ‘Burkini’ Ban in French Town. NY Times [New York] 26Aug16.
  3. Reilly, Katie. Colin Kaepernick Protests National Anthem Over Treatment of Minorities: ‘There Are Bodies in the Street’. Time Magazine, 26Aug16
  4. Cardoso F et al. 70-Gene Signature as an Aid to Treatment Decisions in Early-Stage Breast Cancer, N Engl J Med 2016 Aug 25; 375:8
  5. Reiss-Brennan B, Brunisholz KD, Dredge C, et al. Association of Integrated Team-Based Care With Health Care Quality, Utilization, and Cost [published online August 23/30, 2016]. JAMA. 2016;316(8):826-834.
  6. Carbone M, Mells GF, Pells G, et al.Sex and age are determinants of the clinical phenotype of primary biliary cirrhosis and response to ursodeoxycholic acid. Gastroenterology 2013; 144(3): 560-569
  7. Hirschfield GM, Mason A, Luketic V, et al. Efficacy of obeticholic acid in patients with primary biliary cirrhosis and inadequate response to ursodeoxycholic acid. Gastroenterology 2015; 148(4): 751- 61
  8. Nevens F et al. A placebo-controlled trial of obeticholic acid in primary biliary cholangitis. N Engl J Med 2016 Aug 18; 375:631
  9. Chen LH, Hildegard H, Warner M. Drug-poisoning deaths involving opioid analgesics: United States, 1999-2011. NCHS data brief, no166. Hyattsville, MD: National Center for Health Statistics; 2014.
  10. Walley AY, Xuan Z, Hackman HH, Quinn E, Doe-Simkins M, Sorensen-Alawad A, et al. Opioid overdose rates and implementation of overdose education and nasal naloxone distribution in Massachusetts: interrupted time series analysis. BMJ. 2013;346:f174. [PMID: 23372174] doi:10.1136/bmj.f174
  11. Coffin PO, BeharE, Rowe C, Nonrandomized Intervention Study of Naloxone Coprescription for Primary Care Patients Receiving Long-Term Opioid Therapy for Pain.Ann Intern Med. 2016;165:245-252
  12. Elias,WJ, A Randomized Trial of Focused Ultrasound Thalamotomy for Essential Tremor. N Engl J Med 2016; 375:730-739
  13. Rusthoven CG, Jones BL, Flaig TW, et al: Improved survival with prostate radiation in addition to androgen deprivation therapy for men with newly diagnosed metastatic prostate cancer. J Clin Oncol 34:2835-2842, 2016
  14. Bønaa KH et al. Drug-eluting or bare-metal stents for coronary artery disease. N Engl J Med 2016 Aug 30;




Primecuts – This Week In The Journals

August 22, 2016

rio closing ceremonyBy Anne Press, MD

Peer Reviewed

As the Rio Olympics come to a close this week, we were presented with the best and the worst of the Olympic Games. The world’s focus is surrounding a current scandal related to controversies discussed prior to the Olympics, Brazil’s ability to keep the World’s best athletes safe in a city known for its crime. Last week United States swimmers, including gold medalist Ryan Lochte, came under the spotlight when they recounted a harrowing story of being robbed at gunpoint. This week the scandal continued when it was revealed that the story was in fact fabricated, leading Brazilian authorities to confiscate the swimmers’ passports and prevent them from leaving the country.[1] Another story circulating this week is a heartwarming show of true sportsmanship. USA runner Abbey D’Agostino stopped her own race to help New Zealand runner Nikki Hamblin cross the finish line [2], giving up her chances at a medal. From an uplifting story of selflessness and support exemplifying the Olympics, we turn to the collaborative efforts to help others that is medical research. Here is a look at the major articles in medicine this week.

Extended Thromboprophylaxis with Betrixaban in Acutely Ill Medical Patients

Currently, hospitalized medical patients at high risk for venous thromboembolic (VTE) events are routinely put on prophylactic anticoagulation while hospitalized. However, the risk of fatal VTE events remain elevated for at least a month following hospital discharge.[3] Previous studies have not identified a safe treatment option during this period.[4-6]

A study published this week in the New England Journal of Medicine investigated the role of betrixaban, an oral factor Xa inhibitor, for extended VTE prophylaxis in patients hospitalized with acute medical illnesses.[7] In this randomized, double-blind placebo controlled trial, patients above the age of 40 who were hospitalized for an acute medical illness and had additional VTE risk factors were enrolled. Patients were randomized within 96 hours of admission to subcutaneous enoxaparin plus placebo or subcutaneous placebo plus bertixaban. Enoxaparin or its matching subcutaneous placebo was given for 10 days, and bertixaban or its matching placebo was given for 35-42 days. The primary outcome was a composite of asymptomatic proximal DVT, symptomatic proximal and distal DVT, pulmonary embolism, and fatal VTE events. All patients were followed for 30 days after treatment. During follow up, patients were assessed both clinically with standard VTE testing when indicated and ultrasonography for DVT in asymptomatic patients. For analysis the subjects were evaluated in 3 different cohorts. Cohort 1 was those with an elevated d-dimer, cohort 2 was those with an elevated d-dimer or age >75, and cohort 3 was all enrolled patients. In cohort 1, extended VTE prophylaxis with betrixaban reduced the risk of VTE events compared to placebo but was not statistically significant (RR=0.81; 95% CI=0.65-1.00, P=0.054). In cohorts 2 and 3, subjects treated with betrixaban were found to have a statistically significant decrease in VTE events as well (RR=0.80; 95% CI, 0.66 to 0.98; P=0.03; RR=0.76; 95% CI, 0.63 to 0.92; P=0.00). The results also showed that betrixaban did not result in an increased rate of major bleeding events in this population of patients.

The study was viewed as inconclusive because no statistically significant difference was found in the number of VTE events in the highest risk patients, Cohort 1. An important limitation of this study was that approximately 15% of participants underwent inadequate or no ultrasonography and could not participate in the main analysis. This could have resulted in potential selection bias. The lower number of patients analyzed than anticipated may have also contributed to the lack statistical significance seen in Cohort 1. Overall however, these results have important implications as they suggest that oral betrixaban can be extended safely after discharge and may reduce the rate of VTE among some high-risk patients, though further studies are needed to confirm these findings.


Effects of Large Financial Incentives for Long-Term Smoking Cessation: A Randomized Trial

A common quality metric and routine preventative care measure often encountered in the outpatient primary care setting is smoking cessation. One group of patients which are disproportionally affected are those from lower socioeconomic backgrounds.[8] One proposed means of decreasing smoking rates in this population is large financial incentives, without face-to-face or telephone counseling. However, previous studies have not confirmed a long term effect with this intervention.[9]

A study this week in The Journal of The American College of Cardiology explored this opportunity by studying the long term rates of smoking cessation in the general population after being given a large financial incentive.[10] The single centered, unblinded, randomized parallel group study included 805 smokers over the age of 18 from the lowest third income bracket of Sweden. Patients had to have smoked at least 5 cigarettes everyday for over one year and signed a contract to quit smoking within 1 month in order to participate in the study. The patients were randomized to online counseling or online counseling with finical incentives. The financial incentives were given out in an escalating rewards scheme 6 times during the 6 months. Rewards were given for biochemically verified abstinence with a maximum reward of $1,650. The study’s primary outcome was continuous abstinence between 6 months (when incentives stopped) and 18 months. The results showed a between-group difference of 5.76 percentage points after 18 months (P=0.001), which is similar to the 12-month effects of nicotine gum (6% above placebo), bupropion (5% above placebo), or intensive smoking cessation interventions by physicians (5% above usual care).

These results speak to a possible additional preventative option for patients with regards to smoking cessation. Future studies must further explore the relationship between financial incentives alone versus standard interventional and medical smoking cessation tactics before the role of finical incentives is truly known.

Association Between Achieved Low-Density Lipoprotein Levels and Major Adverse Cardiac Events in Patients With Stable Ischemic Heart Disease Taking Statin Treatment

Current guidelines recommend statin treatment for all patients with preexisting ischemic heart disease (IHD). Despite this, there is no universal agreement regarding target levels of low density lipoprotein cholesterol (LDL-C) in this population.[11,12] Some experts and professional societies, such as The Canadian Cardiovascular Society, recommend a target LDL-C of less than 70.[13] While others, such as the American College of Cardiology, do not recommend a target LDL-C at all.[11,12]

Therefore, an article in JAMA Internal Medicine this week investigated the optimal level of LDL-C in this population of patients.[14] The study was an observational cohort study between the years of 2009-2013. Patients included in the study were aged 30-84 with previous IHD and on statin therapy with at least 80% adherence to treatment. IHD was defined as a previous acute diagnosis requiring secondary prevention including myocardial infarction, unstable angina, percutaneous transluminal coronary angioplasty (PTCA), or coronary artery bypass grafting before the index date. Patients with active cancer or metabolic abnormalities were excluded. The group was divided into those with a “low” LDL-C level of <70, a “moderate” level of between 70-100, and a “high” level of 100-120 as determined as the first achieved serum LDL-C measure after at least one year of statin treatment. The primary outcome included adverse cardiovascular events including acute myocardial infarction, unstable angina, stroke, PTCA, bypass surgery or all-cause mortality. The results showed that there was no different between “low” and “moderate” LDL-C levels (hazard ratio [HR], 1.02; 95% CI, 0.97-1.07; P = .54), but there was a lower number of primary outcomes with “moderate” vs “high” LDL-C levels (HR, 0.89; 95% CI, 0.84-0.94; P < .001).

These results demonstrate that those with an LDL-C level of 70-100 have a lower risk of adverse cardiac outcomes when compared to the “high” LDL-C level group, but there was no additional benefit when a goal of LDL-C below 70 was reached. The limitations of this study included its inclusion of all-cause mortality as a primary outcome, which may be skewed by non-cardiac causes of death. To this end the authors excluded all patients with a history of cancer, a major cause of mortality in Israel, where this study took place. Another important limitation was the inability of the study to account for variability in LDL-C levels, given that LDL-C levels were taken at only one time. Given these aforementioned limitations these results are important as they imply that a target LDL-C for patients with previous IHD, on statin therapy, should be between 70-100 in order to decrease the rates of future adverse cardiovascular events.

Risk of Bleeding and Thrombosis in Patients 70 Years or Older Using Vitamin K Antagonists

Treatment with therapeutic anticoagulation and its associated risk and benefits is a common and difficult decision faced by physicians caring for elderly patients. Previous studies have demonstrated the benefits of anticoagulation in elderly patients; however, these studies have not had an adequate representation of patients in the over 90 age group to prove their overall safety in this population.[15]

Therefore, a study published in JAMA Internal Medicine this week looked specifically at the eldest population’s risk of bleed with vitamin K antagonists (VKA) vs their benefit in decreasing the rates of thrombotic events.[16] This was a matched cohort study of patients at a thrombosis service clinic who were treated with VKA between 2009 and 2012. All patients older than 90 years old were matched with patients in the 80-89 and 70-79 categories. The primary outcome was clinically relevant non-major and major bleeding events and thrombotic events. The study found that the risk of bleeding was not increased in the age 80-89 group (event rate per 100 patient-years [ER], 16.7; hazard ratio [HR], 1.07; 95% CI, 0.89-1.27) and mildly increased in patients 90 years or older (ER, 18.1; HR, 1.26; 95% CI, 1.05-1.50) compared with patients aged 70 to 79 years (ER, 14.8). The risk of developing a thrombosis was higher for patients in their 90s (HR, 2.14; 95% CI, 1.22-3.75) and 80s (HR, 1.75; 95% CI, 1.002-3.05) than for patients in their 70s.

Some limitations of this study included its low number of outcome events, which resulted in wide 95% confidence intervals and therefore leaves some uncertainty regarding the true relative risk. Furthermore, some strokes were classified as ischemic although their true cause was unknown. These limitations not withstanding, the results of this study point to an important lesson in VKA use in the elderly. It seems clear that VKA are needed in this age group since bleeding risk only increased mildly in those ages 90 and over, while there was a sharp increase in thrombotic events in those in those in the same age range.


A study in Circulation highlighted the sexual and ethnic disparities that exist in patients with heart failure being evaluated for an implantable cardioverter-defibrillator. Results showed that women were less likely to be counseled regarding ICD placement than men and racial and ethnic minorities were less likely to receive counseling than white patients.[17]

An article in CHEST investigated a newly developed multidisciplinary Pulmonary Embolism Response Team (PERT) for the treatment of patients with a submissive or massive pulmonary embolism. Results showed that although the PERT team was rapidly adopted the effects on outcome were inconclusive.[18]

A cohort-crossover study described an increased risk of aortic dissection and rupture in pregnant and postpartum patients.[19]

Dr. Anne Press is a 1st year resident at NYU Langone Medical Center

Peer reviewed by Ian Henderson, MD, Medicine, NYU Langone Medical Center

Image courtesy of Wikimedia Commons


  1. Mitchell, Houston. 2016 Summer Olympics live coverage: “Rio police say two swimmers admit Ryan Lochte’s account of gunpoint robbery was false.” Los Angeles Times [Los Angeles]. 19 August 2016:
  2. Rosenbaum, Sophia. “Track collision turns into heart warming Olympic moment.” New York Post [New York]. 16 August 2016:
  3. Amin AN, Varker H, Princic N, Lin J, Thompson S, Johnston S. Duration of venous thromboembolism risk across a continuum in medically ill hospitalized patients. J Hosp Med 2012;7:231-238.
  4. Hull RD, Schellong SM, Tapson VF, et al. Extended-duration venous thromboembolism prophylaxis in acutely ill medical patients with recently reduced mobility: a randomized trial. Ann Intern Med 2010;153:8-18.
  5. Cohen AT, Spiro TE, Büller HR, et al. Rivaroxaban for thromboprophylaxis in acutely ill medical patients. N Engl J Med 2013;368:513-523.
  6. Goldhaber SZ, Leizorovicz A, Kakkar AK, et al. Apixaban versus enoxaparin for thromboprophylaxis in medically ill patients. N Engl J Med 2011;365:2167-2177.
  7. Cohen AT, Harrington RA, Goldhaber SZ, et al. Extended Thromboprophylaxis with Betrixaban in Acutely Ill Medical Patients. N Engl J Med. 2016;375(6):534-44.
  8. M. Huisman, A.E. Kunst, J.P. Mackenbach. Inequalities in the prevalence of smoking in the European Union: comparing education and income. Prev Med, 40 (2005), pp. 756–764
  9. K. Cahill, J. Hartmann-Boyce, R. Perera. Incentives for smoking cessation. Cochrane Database Syst Rev, 4 (2015), p. CD004307
  10. Troxel AB, Volpp KG. Effectiveness of financial incentives for longer-term smoking cessation: evidence of absence or absence of evidence?. Am J Health Promot. 2012;26(4):204-7.
  11. Amsterdam  EA, Wenger  NK, Brindis  RG,  et al; ACC/AHA Task Force Members; Society for Cardiovascular Angiography and Interventions and the Society of Thoracic Surgeons.  2014 AHA/ACC guideline for the management of patients with non-ST-elevation acute coronary syndromes: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines [published correction appears in Circulation. 2014;130(25):e431-e432]. Circulation. 2014;130(25):2354-2394.
  12. Steg  PG, James  SK, Atar  D,  et al; Task Force on the management of ST-segment elevation acute myocardial infarction of the European Society of Cardiology (ESC).  ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. Eur Heart J. 2012;33(20):2569-2619.
  13. Anderson, et al. 2012 update of the Canadian Cardiovascular Society guidelines for the diagnosis and treatment of dyslipidemia for the prevention of cardiovascular disease in the adult. Can J Cardiol. 2013 Feb;29(2):151-67.
  14. Leibowitz M, Karpati T, Cohen-stavi CJ, et al. Association Between Achieved Low-Density Lipoprotein Levels and Major Adverse Cardiac Events in Patients With Stable Ischemic Heart Disease Taking Statin Treatment. JAMA Intern Med. 2016;176(8):1105
  15. Fihn  SD, Callahan  CM, Martin  DC, McDonell  MB, Henikoff  JG, White  RH; The National Consortium of Anticoagulation Clinics.  The risk for and severity of bleeding complications in elderly patients treated with warfarin. Ann Intern Med. 1996;124(11):970-979.
  16. Kooistra HA, Calf AH, Piersma-wichers M, et al. Risk of Bleeding and Thrombosis in Patients 70 Years or Older Using Vitamin K Antagonists. JAMA Intern Med. 2016;176(8):1176-83.
  17. Hess PL, Hernandez AF, Bhatt DL, et al. Sex and Race/Ethnicity Differences in Implantable Cardioverter-Defibrillator Counseling and Use Among Patients Hospitalized With Heart Failure: Findings from the Get With The Guidelines-Heart Failure Program. Circulation. 2016;134(7):517-26.
  18. Kabrhel C, Rosovsky R, Channick R, et al. A Multidisciplinary Pulmonary Embolism Response Team: Initial 30-Month Experience With a Novel Approach to Delivery of Care to Patients With Submassive and Massive Pulmonary Embolism. Chest. 2016;150(2):384-93.
  19. Kamel H, Roman M, Pitcher A and Richard B. Pregnancy and the Risk of Aortic Dissection or Rupture. Circulation. 2016;134:527-533.


Primecuts – This Week In The Journals

August 15, 2016

Rio_2016_Brasil_x_AdS_BSB_7946By Karen McCloskey, MD

Peer Reviewed 

The world’s eyes were on Rio as the 2016 Summer Olympics wrapped up its first full week of competition. In the lap pool (fortunately not green, like the diving pool), United States swimmers had a fantastic games; Michael Phelps continued to demonstrate why he is the most decorated Olympian of all time, closing out his Olympic career with 28 medals, with 5 of his 23 gold medals earned in Rio (along with one silver).1 Katie Ledecky blew away the competition in women’s freestyle (finishing the 800m race nearly 12 seconds before the second-place winner), and Simone Manuel became the first African-American female swimmer to win an individual gold medal.

On land, Simone Biles stunned with her moves on the gymnastics floor, the uniforms of Egypt’s women’s beach volleyball team prompted discussions on culture, and Fiji’s rugby sevens side won the country’s first Olympic medal, and made it a gold.2

From awe-inspiring athletic achievement, we turn our attention to medicine, looking at some of this week’s most interesting literature: 

Randomized Trial of Thymectomy in Myasthenia Gravis

About 10% of myasthenia gravis patients have thymomas that must be resected to prevent further spread of the disease3. Of the remaining patients, about 70% of patients have hyperplastic changes of the thymus that are not seen in healthy individuals4,5. Even in non-thymomatous myasthenia gravis patients, thymectomies have been performed for several decades, though rates of have declined over the last 15 years.6  Several retrospective studies and observational studies have been performed to examine the benefit of thymectomy in non-thymomatous myasthenia gravis, with promising, but inconsistent results.  However, a systematic review was undertaken looking at 21 such studies, and it was determined that the amount of methodologic flaws in these studies precluded making a definitive recommendation based on those results.7

The Thymectomy Trial in Non-Thymomatous Myasthenia Gravis Patients Receiving Prednisone Therapy (MGTX) was published in the New England Journal of Medicine this week by Wolfe, et al. – it was an international randomized, single-blinded trial conducted by the National Institute of Neurological Disorders and Stroke (NINDS) to evaluate whether thymectomy combined with a standardized prednisone protocol was superior to prednisone therapy alone.8  The end points were lessening of myasthenic weakness, lower total doses of prednisone (given the high potential for side effects with glucocorticoid therapy), and improved quality of life.  Participants were recruited from 67 centers in 18 countries (about half in the United States).  6958 patients were screened, with 2126 ultimately randomized.  Inclusion criteria required a duration of myasthenia gravis less than 5 years; age of 18 to 65 years; certain antibody levels, as well as Myasthenia Gravis Foundation of America clinical classification of II-IV (representing mild, moderate, and severe generalized disease without crisis).  Participants were allowed to be taking anticholinesterase therapy with or without oral steroids.  Relevant exclusion criteria were thymoma on imaging or immunotherapy (besides prednisone).  Participants were randomized to prednisone-only versus thymectomy groups.  Those undergoing thymectomy had median sternotomy resection of all mediastinal tissue that could contain gross or microscopic thymus.

The results showed that patients in the thymectomy did better on all measured outcomes: a lower Quantitative Myasthenia Gravis score (representing improvement in overall disease symptoms) 6.15 vs 8.99 for the prednisone-only group (p<0.001, 95% CI 0.47 to 5.22) and lower average required prednisone dose (44mg vs 60mg based on standardized, alternatve-day dosing, p<0.001,95% CI, 7 to 25).  In terms of quality of life, participants in the thymectomy group had fewer adverse reactions due to immunosuppressive medications, and 9% vs 37% (p<0.001) rate of hospitalizations for exacerbations.

This study showed a clear benefit to thymectomy in non-thymomatous myasthenia gravis, in terms of clinical status, prednisone dose (as well as adverse effects of immunosuppressive medications) and rate of hospitalizations for myasthenia exacerbations. Though the procedure itself is substantial, requiring median sternotomy, it appears the long-term affects of thymectomy are very positive for patients with myasthenia gravis.

Risk of lymphoma in patients exposed to antitumour necrosis factor therapy: results from the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis

Biological agents like the Tumor Necrosis Factor inhibitors revolutionized the treatment of autoimmune diseases such as RA when they were introduced in the 1990s9–11However, there have been some concerns that these medications, due to their suppression of a key portion of the inflammatory pathway, might increase the risk of lymphoma development in patients with rheumatoid arthritis (RA).12 RA patients already have increased lymphoma risk13,14 thought to be due to the inflammatory nature of their disease.15  Conversely, it is possible that TNF inhibitors may, by way of inflammatory suppression, reduce the lymphoma risk in RA patients.

In the current issue of Annals of Rheumatic Diseases, the British Society for Rheumatology (BSR) led by Mercer et al., conducted a prospective cohort study using the data from the British Society for Rheumatology Rheumatoid Arthritis Register (BSRBR-RA).16  This register was established in 2001 in order to track, principally, the association between TNF inhibitors and development of lymphoma.  Patients were separated into two cohorts, one biologic naïve group and the other biologic non-naïve.  In the UK, TNF-I use is restricted to patients with highly active disease (based on a standardized Disease Activity Score) despite treatment with at least two non-biological disease-modifying drugs (csDMARDs).  Once patients were enrolled with the BSRBR-RA, based on data collected from rheumatologists, they were also flagged in the national cancer registries (National Health Service Information Centre or Northern Ireland Cancer Registry).  These cancer registries notified the BSRBR-RA if enrolled patients had a history of cancer or developed cancer after being registered.  Patients were then followed until death or self-withdrawal from the study.  Patients were excluded if they had prior diagnosis of lymphoproliferative or myeloproliferative malignancy, or if they had exposure to biological agents prior to enrollment.  Available biologic agents at the time of the study were etanercept (ETA), infliximab (INF), and adalimumab (ADA).

The results showed that the 3,367 biological-naïve patients (treated with csDMARDs only) and the 11,931 showed no significant difference in the rate of lymphoma over the median 6.5 years of follow-up time. The results were calculated in patient-years with 154 cases per 100,000 (95% CI=104 to 220) in the 19,473 patient-years of the csDMARD group versus 88 cases per 100,000 (95% CI=70 to 109) in the biological group.  When adjusted for confounders, the hazard ratio between these groups was 1.00 (95% CI 0.56 to 1.80).  Each individual TNF-I was also evaluated and none demonstrated either increased or decreased risk of lymphoma.

This study provides a large-scale demonstration that there appears to be no increased risk of lymphoma when using TNF-I, helping rheumatologists feel safe in prescribing these very effective medications. Previous studies have shown mixed results in regard to this effect.17,18The large enrollment numbers and the advantage of the high percentage of disease capture due to the nature of the national registries give credence to the robustness of this study. The two main drawbacks of this study were insufficient power to detect the risk of individual subtypes of lymphoma, and the relatively short monitoring time, with the study tracking only up to 5 years after treatment initiation.  This may not be a long enough period of treatment to detect medication-associated cancer risk.  Further research studying larger populations, and with longer follow-up time, is needed to determine long-term lymphoma risk using these biological agents.

Association Between Occupational Exposures and Sarcoidosis: An Analysis From Death Certificates in the United States, 1988-1999

Mortality related to sarcoidosis has been increasing over the past several decades.19,20While the etiology of sarcoidosis has not been fully elucidated yet, the prevailing theory is that some environmental or occupational exposure triggers the disease in genetically susceptible individuals.21,22 Prior studies have examined the relationship between sarcoidosis and certain, select occupations (eg, firefighters23, navy recruits24, etc.), however no study has looked at the association of sarcoidosis using lifetime occupational data.

A study published in Chest this week by Liu et al, aimed to determine the association between sarcoidosis mortality and occupational exposures.25 Some of the basis of this study was to determine if previously studied gender differences in sarcoidosis rates (women are affected more frequently than men26) could be attributable to occupational disparities, or if occupational exposures imposed greater risk on women than men. These same questions were addressed taking into account racial differences as well.

The study used death certificate data from 1988 through 1999 as compiled by the National Center for Health Statistics from the 25 states that included Occupational Classification Codes during the studied time period. The researchers analyzed this data for exposures and job titles that had been found in prior research to have an association to sarcoidosis.

A total of 7,118,535 patients over age 14 found 3,393 sarcoidosis-related deaths, with an even ratio of men to women; however, sarcoidosis-related mortality was higher for woman than men with an adjusted mortality odds ratio (MOR) of 2.25 (95% CI, 2.10-2.42).   The study also found a sarcoidosis-related MOR of 1.52 of any occupational exposure versus no occupational exposure (95% CI, 1.35-1.71), with an increased risk for women with exposure vs women without (MOR 1.65, 95% CI 1.45-1.89).  Implicated occupations were metal working, health care, teaching, sales, banking and administration.  For certain occupations, the sarcoidosis-related mortality risks were high for blacks vs whites as well (ie, sarcoidosis-related deaths in healthcare fields had an MOR of 10.73 in black versus white subjects, 95% CI, 7.03-12.46).  The study postulates that occupations related to “possible inhalational exposures” were associated with greater sarcoidosis-related mortality in men, while occupations related to “person-to-person contact” were associated with sarcoidosis-related mortality in women, and that this may correlate to previous findings that women are more prone to skin and eye involvement (contact-susceptible organs), while men are more prone to cardiac and pulmonary involvement (inhalation-suspectible organs)27–29Race differences are potentially related to genetic susceptibility.

While this study helps advance the research pointing to occupational-related sarcoidosis by its scale and breadth, it does leave some questions unanswered. Presumably, this study uses the term “no exposure” to mean occupations not previously shown to have sarcoidosis-related exposure risk; however, it could also mean subjects for whom no occupational data was available on death certificates – the manuscript is not clear on this point.  In the former scenario, the presumption that all previously unstudied occupations pose no increased risk of sarcoidosis leaves the data open to confounding by occupations that have increased risk, but have not yet been identified in the literature.  In the unlikely latter scenario, comparisons will have been made to a completely undefined control group.  However, the study does advance the sarcoidosis-related research with regards to occupational exposure, which helps direct future research attempting to elucidate mechanisms of disease.  It may also allow for better occupational safety standards in affected occupations.

Effect of a Cerebral Protection Device on Brain Lesions Following Transcatheter Aortic Valve Implantation in Patients With Severe Aortic Stenosis: The CLEAN-TAVI Randomized Clinical Trial

Transcatheter aortic valve implantation (TAVI) has allowed many high-risk patients the opportunity for a less-invasive procedure than an open surgical approach, with recent data suggesting a mortality benefit in TAVI patients.30 Unfortunately, stroke risk in aortic valve replacement patients, whether using surgical or transcatheter approaches, remains high – as many as 80% of TAVI patients are found to have new ischemic lesions on diffusion-weighted MRI31,32Several devices designed to prevent embolic debris from reaching the brain have been developed, with trends showing decreased number of ischemic lesions when these devices are used, however none have shown statistical significance.33

JAMA this week published results from the Claret Embolic Protection and TAVI (CLEAN-TAVI) from the University of Leipzig, a single-center, blinded, randomized control trial of 100 patients, to determine the efficacy of the Claret Montage Dual Filter System for cerebral protection.34 The Leipzig Heart Center, where this study was conducted, received a grants from Claret Medical as well as Medtronic (replacement valves were Medtronic CoreValves). The study included patients with severe, symptomatic aortic stenosis who were considered high-risk for surgical valve replacement. Exclusion criteria were pre-existing pacemaker, stroke within the previous 12 months, significant carotid, right subclavian or braciocephalic trunk stenosis, or anatomy unsuitable for TAVI.

Baseline MRI was compared to MRI at days 2 and 7 post-procedure. The primary end point was reduction in the number of new post-procedure on day 2 diffusion-weighted MRI (DWMRI). The group hypothesized that the cerebral protection device would lead to 50% reduction in new lesions on day 2 DWMRI in the regions protected by the cerebral protection filter. Results showed that TAVI was associated with DWMRI-positive brain lesions in 98% of patients in both the filter and the control groups, however the number of lesions was lower in the filter group (4.00 versus 10.00, difference 5.00, interquartile range 2.00-8.00, P<0.001). Secondary analysis showed that new lesion volume in the filter group was 242 mm3 (95% CI 159-353mm3, significantly lower than the 527mm3 (95% CI, 364-830) in the control group (difference of 234mm3, 95% CI, 91-406, P=0.001).   In both groups, 5 patients demonstrated neurologic symptoms of stroke, though all were minor and non-disabling.

While this study demonstrates a lower radiologic stroke burden in patients using this cerebral protection filter, it does not clearly show a clinical benefit to the use of this device. An equal number of patients in both groups showed neurologic manifestations of stroke, and all were minor. This study shows that there is some promise in the use of cerebral protection devices to reduce the stroke rate in TAVI, but a great deal more research is needed to demonstrate any clinical benefit before these devices become part of standard practice.


For the first time, a joint statement was published for the treatment of Type 2 Diabetes that included indications for when to recommend or consider bariatric surgery for patients as part of treatment for the disease.35

In a post-hoc analysis of the RE-LY trial (which looked at dabigtran versus warfarin in non-valvular atrial fibrillation) found that for patients with valvular heart disease (excluded by the original study) dabigitran carried a lower stroke risk and lower risk of significant bleeding as compared to warfarin.36

Finally, the US Preventive Services Task Force released guidelines on screening for dyslipidemia in young adults, aged 21-39, which showed that no study has examined the effects of lipid screening versus no screening in this age group, and therefore the Task Force is unable to recommend for or against screening at this time.37

Dr. Karen McCloskey is a 1st year resident at NYU Langone Medical Center

Peer reviewed by Kevin Hauck, MD, associate Editor, Clinical Correlations

Image courtesy of Wikimedia Commons


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  36. Ezekowitz MD, Nagarakanti R, Noack H, et al. Comparison of Dabigatran versus Warfarin in Patients with Atrial Fibrillation and Valvular Heart Disease: The RE-LY Trial. Circulation. 2016.
  37. Chou R, Dana T, Blazina I, Daeges M, Bougatsos C, Jeanne TL. Screening for Dyslipidemia in Younger Adults: A Systematic Review for the U.S. Preventive Services Task ForceScreening for Dyslipidemia in Younger Adults. Ann Intern Med. 2016;N/A(N/A):N/A – N/A.






Primecuts – This Week In The Journals

August 10, 2016

Olympic_Trials_2016 By Nathan Teich, MD

Peer Reviewed

This week, Rio de Janeiro hosts the XXXI Summer Olympics games which had its official opening ceremonies on August 5th, 2016. Many controversies surround the games including doping scandals and concerns about safety in the host city [1]. However, many positives are also highlighted by the games, including athletes such as Syrian refugee Yusra Mardini whose Olympic journey includes her and another refugee pulling an overloaded dinghy across the Mediterranean to Greece saving the lives of 20 other people [2]. Other Olympic athletes return to represent their countries and push the limits of what is physically possible. From the global unity of athletic competition to medicine, we look at articles from around the world that offer hope for devastating diseases and potential changes to clinical practice.

Sickle Cell Trait, Rhabdomyolysis, and Mortality among U.S. Army Soldiers

Exertional rhabdomyolysis resulting from the breakdown of muscle tissue has been implicated in deaths involving athletes and military members. Sickle cell trait is a common hemoglobin mutation affecting 1.6% of the US population and 7.3% of black individuals and has been associated with an increased risk of rhabdomyolysis in affected persons exposed to demanding physical exertion [3]. Previous population-based studies have shown higher rates of death among black military recruits but have not adequately examined if sickle cell trait was present in those who died. The NCAA and United States Air Force have instituted universal screening for sickle cell trait, but concerns have been raised about the possibility of stigmatization of affected patients, particularly in the absence of evidence that screening prevents adverse events [4,5].

This week in the New England Journal of Medicine, a study was published that attempted to quantify the associations between sickle cell trait and death and exertional rhabdomyolysis [6]. This was a retrospective cohort study that examined data from the Stanford Military Data Repository (SMDR), a database of all health encounters for active-duty soldiers in the US Army. The records of 47,944 black soldiers who served at any time in active duty from Jan 2011 to Dec 2014 who had undergone HbAS testing before or during this time were included.  Main outcomes were exertional rhabdomyolysis and death. Cases were identified using ICD-9 codes for rhabdomyolysis and myoglobinuria.  Other cases due to trauma or toxicity were excluded. Sex, age, physical fitness (using army fitness testing), tobacco use, and drugs that may lead to rhabdomyolysis (statins, antipsychotics, stimulants) were identified as individual variables.

7.4% of the study population had sickle cell trait. 391 episodes of exertional rhabdomyolysis were identified over 1.61 million person months. Presence of sickle cell trait was associated with a 54% higher risk of exertional rhabdomyolysis compared with the absence of the trait (HR 1.54; 95% CI, 1.12 to 2.12; p=0.008). 96 deaths were noted among the study participants with no significant difference between those with and without sickle cell trait (HR 0.99; 95% CI 0.46 to 2.13, p=0.97). Women were at lower risk than men (HR 0.51; 95% CI 0.38 to 0.67; P<0.001). Those with age greater than 36 were at higher risk (HR 1.57; 95% CI 1.06 to 2.32; P=0.02). Obesity (HR 1.39; 95% CI 1.04 to 1.86; p=0.03), tobacco usage in the past 6 months (HR 1.54; 95% CI, 1.23 to 1.94; P<0.001), antipsychotic usage (HR 3.02; 95% CI, 1.34 to 6.82; P = 0.008), and statin usage (HR 2.89; 95% CI, 1.51 to 5.55; P = 0.001) were all associated with increased risk of exertional rhabdomyolysis.

This study suggests that there is no association between sickle cell trait and death, but there is a small excess risk for exertional rhabdomyolysis. The policy implications of these results in terms of preventing exertional rhabdomyolysis are not clear, given the small absolute increase in excess risk and that use of statins or antipsychotics conferred greater risk.  The study was limited by using ICD-9 codes to identify cases of rhabdomyolysis, as well as possible selection bias, in that individuals may have had an episode of exertional rhabdomyolysis prior to the study leading to their medical discharge. Also, universal screening for sickle cell trait is not standard practice in the Army, so the study may underreport cases associated with the trait.

Association Between Off-site Central Monitoring Using Standardized Cardiac Telemetry and Clinical Outcomes Among Non–Critically Ill Patients

Frequent telemetry alarms in non-ICU level patients lead to alarm fatigue and are without clinical significance in the vast majority of cases. Dedicated nursing to monitor telemetry alarms is associated with improved recognition of true rhythm events but these are often missed amidst the din of a hospital ward [7]. Inappropriate use of telemetry in patients without indications for it increases costs markedly and adds to alarm fatigue at the expense of recognition of true arrhythmic events.  The implementation of dedicated off-site telemetry monitoring along with standardization of telemetry utilization protocols have been proposed as methods of improving the recognition of true alarms and decreasing alarm fatigue by eliminating the distractions of the hospital environment.

This week in the Journal of the American Medical Association, a study was published examining outcomes from cardiac telemetry monitored at an off-site central monitoring unit (CMU) in non-ICU level patients at a major academic center and 3 regional hospitals. One telemetry nurse monitored up to 48 patients and were able to remotely activate Emergency Response Teams (ERT). Standardization of cardiac telemetry was also undertaken based on guidelines from 2004 American Heart Association necessitating electronic order with indication and advisory to document need for renewal at 72 hours. Total telemetry census was monitored in addition to the primary outcome of ERT activation within one hour based on rhythm and rate alarms. Total number of cardiopulmonary arrests were also tracked.  Data from the 13 month period prior the intervention was compared to the 13 month period post-intervention to generate study outcomes.

Telemetry orders were placed for 99,048 patients with the most common indication (16%) being known or suspected atrial or ventricular arrhythmia. The “other” category also made up 16% of telemetry orders with the most common free-text being monitoring for hypotensive state. The standardization of telemetry was associated with a 15.5% reduction in the weekly telemetry census compared to the preceding 13 month period and persisted throughout the study. The number of cardiopulmonary arrests was 126 pre-intervention and 122 post-intervention. The majority of calls (80%) were noted to be for lead failure.

During the study period, 3243 ERT activations occurred on telemetry monitored patients in which 979 had a detectable rate or rhythm change 1 hour prior to ERT activation. The central monitoring unit notified nursing staff in 772 of these 979 cases appropriately. In the remaining 207 patients that went without notification, 176 were missed events, 16 were alarms with simultaneous activation of the ERT, and 15 were process failures. Many of the missed events were due to rapid activation of the ERT by clinical staff or for minor HR changes of 10-20 which may be of no clinical significance.

In 105 events, the CMU directly activated the ERT in parallel to nursing. 44 of these events were monomorphic ventricular tachycardia, 36 were prolonged pauses/asystole, 14 were polymorphic ventricular tachycardia or fibrillation and 11 were other. 27 of these episodes were CPR events.

This study indicates that off-site telemetry monitoring may be a useful adjunct to current clinical practice as there was no change in cardiopulmonary arrests and a reduction in the weekly telemetry census. However, alarm fatigue remains an issue as 80% of calls from the CMU to the nursing unit were for lead failure. Furthermore, this study which was performed at a large tertiary center may be difficult to generalize to smaller or rural hospitals. [8]

Immunoablation and autologous haemopoietic stem-cell transplantation for aggressive multiple sclerosis

In multiple sclerosis, an acquired inflammatory autoimmune disease targeting the central nervous system, use of immune modulating therapies to target inflammation has had some success, however there is ultimately relapse and progression. Autoimmune disease regression in patients undergoing haemopoetic stem cell transplant (HSCT) for malignancy have been noted in previous studies [9]. Given this potential benefit, a phase 2 single arm study at 3 Canadian hospitals enrolled patients with a poor prognosis (early relapse, high probability of progression, disability) to undergo busulfan, cyclophosphamide, and anti-thymocyte globulin for immune-ablation and destruction of immunological memory followed by autologous HSCT, with the desired goal of eliminating CNS autoimmunity while still ensuring adequate immune function. Baseline and frequent interval follow-up MRI with gadolinium were performed to follow lesions along with evaluation of the Expanded Disability Status Scale (EDSS). Primary outcomes were MS activity-free survival at 3 years with events including: clinical relapse, new MRI lesions or progression on the EDSS. Secondary outcomes were time to treatment failure and overall morbidity and mortality due to HSCT. 24 patients with active disease underwent HSCT from 2001 to 2009.

The primary outcome of multiple sclerosis activity free survival at 3 years was 69.6% (95% CI 46.6-84.2) mainly driven by sustained progression in Expanded Disability Status Scale. From diagnosis of MS to transplantation, there were 167 relapses in 24 patients (mean 1.2 relapses per patient year). Following transplantation, there were no episodes of clinical relapse in any of the 23 patients who survived HSCT (0.0 relapses per patient year). There were 93 and 95 Gadolinium enhancing lesions on the two pre-treatment MRIs. After HSCT, none of the 327 follow-up scans showed Gadolinium enhancing lesions. One patient died due to hepatic necrosis and Klebsiella sepsis secondary to Busulfan dosing, which was adjusted during the trial to prevent further medication-related side effects.  Following HSCT, 6 patients (26%) suffered shingles, and 6 patients (26%) suffered secondary autoimmune events.

These results suggest that HSCT can result in lasting disease remission in patients with unrelenting, refractory MS. Though these a results are promising, a prospective randomized trial is needed to evaluate this therapy as a mainstay of treatment.  Notable limitations in the study include the lack of control group and that this was a small study cohort. The authors note that patient selection is key, given that previous studies with relapse occurred in patients without clear evidence of ongoing inflammatory disease secondary to MS [10].


A multi-center open label randomized controlled study at 10 pulmonary clinics in northern Vietnam found that point of care C-reactive protein testing reduced the use of antibiotics in acute respiratory tract infections without affecting patient recovery [11]

In a large chronic heart failure cohort taking statins there was no significant difference in exercise tolerance, aerobic capacity, and quality of life. This contrasts previous studies indicating decrease in exercise tolerance during statin usage [12]

Inflammatory bowel disease patients are 33% more likely to experience recurrent Clostridium difficile infection (rCDI) compared to the general population in the RECIDVISM study. Exposure to antibiotics, 5-ASA, certain biologics (Infliximab) are predictors of rCDI, along with having non-ileal Crohn’s disease [13]

Nathan Teich, MD is a second year internal medicine resident at NYU Langone Medical Center

Peer reviewed by Benjamin Milgrom, MD Associate Editor, Clinical Correlations

Image courtesy of Wikimedia Commons


  1. Tom McGowan, John Sinnott, Eoghan Macguire and Shasta Darlington. Rio Olympics: Is Brazil ready for the 2016 Games? CNN. July 30 2016.
  2. Jon Schuppe, and Kelly Cobiella. How Yursa Mardini Survived a 25-Day Trek From Syria And Became an Olympia. NBC News. August 5 2016. 
  3. Kark JA, Posey DM, Schumacher HR, Ruehle CJ. Sickle-cell trait as a risk factor for sudden death in physical training. N. Engl. J. Med. 317: 781-7 (1987).
  4.  Diggs, L. W. The sickle cell trait in relation to the training and assignment of duties in the armed forces: IV. Considerations and recommendations. Aviat. Space Environ. Med. 55, 487-492 (1984).
  5.  Harmon, K. G., Drezner, J. A., Klossner, D. & Asif, I. M. Sickle cell trait associated with a RR of death of 37 times in National Collegiate Athletic Association football athletes: a database with 2 million athlete-years as the denominator. Br. J. Sports Med. 46, 325-330 (2012).
  6.  Nelson, D. A. et al. Sickle Cell Trait, Rhabdomyolysis, and Mortality among U.S. Army Soldiers. N. Engl. J. Med. 375, 435-442 (2016).
  7. Stukshis, I., Funk, M., Johnson, C. R. & Parkosewich, J. A. Accuracy of detection of clinically important dysrhythmias with and without a dedicated monitor watcher. Am. J. Crit. Care 6, 312-317 (1997).
  8. Cantillon, D. J. et al. Association Between Off-site Central Monitoring Using Standardized Cardiac Telemetry and Clinical Outcomes Among Non-Critically Ill Patients. JAMA 316, 519-524 (2016).
  9. Arruda, L. C. et al. Resetting the immune response after autologous hematopoietic stem cell transplantation for autoimmune diseases. Curr. Res. Transl. Med. 64, 107-113 (2016).
  10. Atkins, H. L. et al. Immunoablation and autologous haemopoietic stem-cell transplantation for aggressive multiple sclerosis: a multicentre single-group phase 2 trial. Lancet (2016).
  11. Do, N. T. et al. Point-of-care C-reactive protein testing to reduce inappropriate use of antibiotics for non-severe acute respiratory infections in Vietnamese primary health care: a randomised controlled trial. Lancet Glob. Health. (2016).
  12. Kelly, J. P. et al. Statins and Exercise Training Response in Heart Failure Patients: Insights From HF-ACTION. JACC Heart Fail. 4, 617-624 (2016).
  13. Razik, R., Rumman, A., Bahreini, Z., McGeer, A. & Nguyen, G. C. Recurrence of Clostridium difficile Infection in Patients with Inflammatory Bowel Disease: The RECIDIVISM Study. Am. J. Gastroenterol. 111, 1141-1146 (2016).


Primecuts – This Week In The Journals

August 1, 2016

450px-Starr_080607-7119_Rosa_sp_By Christopher Sonne , MD

Peer Reviewed

This week, Hillary Clinton became the first woman to accept the presidential nomination of a major political party. Her acceptance came on the final day of the 2016 Democratic National Convention (DNC) in Philadelphia. After eight years as first lady, eight years as senator and four years as US Secretary of State, she delivered what some would consider to be one of her most important political speeches. In it she called for party and national unity, and stated as the first woman presidential nominee, “When any barrier falls in America, for anyone, it clears the way for everyone” [1]. Her acceptance comes on the heels of an email hack that revealed an embarrassing firestorm of comments from high-ranking DNC officials to help propel Mrs. Clinton past challenging democrat Senator Bernie Sanders. The hack had been ongoing for many months via undetected malware on DNC computers, and likely linked to two independent Russian hacking groups [2]. From politics to medicine, we look at articles this week about medications with new promises, new warnings, and considerations in the realm of public health.

Non-Selective Beta-Blockers and Survival in Patients with Cirrhosis and Ascites

Non-selective beta-blockers (NSBBs) have historically played a prominent role in the primary and secondary prevention of variceal bleeds in patients with cirrhosis. Their role in decreasing the risk of first variceal bleed alone and in decreasing risk of second variceal bleed in conjunction with endoscopy vs endoscopy alone has been well established in several high-quality randomized control trials [3,4]. Surprisingly, two studies by Sersté [5,6] have identified limitations of NSBBs particularly in patients with refractory ascites showing an increase in mortality. This finding was thought to be secondary to circulatory dysfunction in patients with frequent paracenteses. These randomized control trials (RCT’s) were however underpowered to evaluate this specific population.

This week in the journal of Clinical Gastroenterology and Hepatology, Sakkarin et al. published a systematic review and meta-analysis to assess all-cause mortality in patients with cirrhosis with ascites. For their review they pulled data on 3145 patients with established cirrhosis and ascites from 3 RCT’s and 8 observational studies and divided these patients between those who received beta-blockers as prevention for variceal bleeds (propranolol, carvedilol, nadolol, and metoprolol) vs. those who received other interventions to prevent variceal bleeds. The major end-point was mortality. When considering data from all 11 articles, there was no association between NSBB use and all-cause mortality, but there was considerable heterogeneity between studies (I2 94%; P < .00001). In subgroup analysis of only the 3 RCT’s, NSBB use was not associated with increased all-cause mortality; no heterogeneity was seen (RR 1.02; 95% CI, 0.63 – 1.67; P = 93; I2 = 0%, P = .44). When the authors again tried to limit their subgroup analyses of patients only with refractory ascites, they found no mortality difference but again encountered significant unexplained heterogeneity. Notably, the meta-analysis did demonstrate that the mortality rate in cirrhotic patients with refractory ascites had a poor prognosis regardless of treatment with or without NSBBs [7].

Though the study was not able to answer the question of NSBB use in cirrhotics with refractory ascites with a high degree of certainty, results from the review imply that providers should not routinely withhold NSBBs from cirrhotics with ascites, but should be aware of the risks and benefits of NSBB use.

The FDA Updates Warnings on Fluoroquinolone Use Claiming Disabling Side Effects

This week the FDA revised the Boxed Warning, the “FDA’s strongest warning”, on nearly the entire class of Fluoroquinolones (moxifloxicin, ciprofloxicin, gemifloxacin, levofloxacin, and ofloxacin). The update was made to address the growing concern over the drugs’s association with musculoskeletal, peripheral neuropathy, and central nervous system side effects. The warning states that these fluoroquinolones should be “reserved for use in the patients who have no other treatment options for acute bacterial sinusitis, acute exacerbation of chronic bronchitis, and uncomplicated urinary tract infections” in which the benefits of the antibiotic would not necessarily outweigh the risk.

The update most specifically addresses a warning for the risk of potentially permanent peripheral neuropathy in adults, a finding that became a concern after an initial 2013 FDA review. Following the 2013 review, the FDA has been tracking post-marketing reports of “apparently healthy patients who experienced disabling and potentially permanent side effects” after systemic treatment with a fluoroquinolone. The FDA’s recommendations to providers is to immediately stop the use of the drug if a patient reports adverse side effects while on a fluoroquinolone, and to switch to a non-fluoroquinolone antibiotic to finish an antibiotic course. [8].

LEADER Trial demonstrates Liraglutide’s Non-inferiority to Placebo in Cardiovascular Death, But Lacks Heart Failure Data

Liraglutide is an injectable glucagon-like peptide 1 (GLP-1) analogue for the treatment of patients with Type 2 diabetes. With recent concern coming from a 2014 Lancet meta-analysis that glycemic control by antihyperglycemic medications may increase the risk of heart failure [9], the LEADER trial was developed to test cardiovascular outcomes for patients on liraglutide. The LEADER trial was a randomized double-blinded control trial that set out to establish the drug’s non-inferiority to placebo (though superiority analyses were also reported). It recruited over 9,000 adults with type 2 diabetes and had a composite primary endpoint made up of “death from cardiovascular cause”, nonfatal myocardial infarction (AMI), or non-fatal stroke. For patients who had hemoglobin A1c’s >7.0 after randomization, additional glucose control medications were allowed with the exception of other GLP agonists, DPP-4 inhibitors, or pramlintide. Data collection lasted for 54 months.

There was a significant reduction compared to placebo in the trials composite primary endpoint (HR 0.87, 95% CI 0.78-0.97, P=0.01). In the article’s displayed results of the individual endpoints, nonfatal myocardial infarction and nonfatal stroke in the liraglutide group showed no statistical difference compared to the placebo group (HR 0.88; 95% CI 0.75-1.03, P=0.11 for non-fatal AMI; HR 0.89, 95% CI 0.72-1.11, P=0.30 for non-fatal stroke). The driving difference for the primary endpoint came from the “death from cardiovascular causes” (HR 0.78, 95% CI 0.66-0.93, P=0.007). Definitions of “death from cardiovascular causes” were not included in the original article, but were accessible via the Supplementary Appendix, from which the definition of “death from cardiovascular causes” included sudden cardiac death, death due to acute myocardial infarction, death due to heart failure, death due to stroke, and death due to other cardiovascular causes (10). All patients who underwent randomization were included in the analysis of the primary outcome. P-values above were from a secondary superiority statistical analysis.

Notably, while the “death from cardiovascular cause” definition included death due to heart failure, no data were reported specifically for heart failure deaths or hospitalizations due to heart failure. This is worth noting as the original concern for cardiovascular risk in antihyperglycemic medications involved the increased risk of heart failure. Nonetheless, this large trial does convincingly demonstrate non-inferiority in cardiovascular deaths with use of liraglutide compared to placebo. The trial was funded by liraglutide pharmaceutical Novo Nordisk [11].

Estimating the Global Economic Burden of Physical Inactivity

The detrimental health effects of physical inactivity has become glaringly apparent. As physicians battle these effects on the front lines of their offices and hospital rooms, governments around the world have begun to enter the fray recognizing the impact that resulting health effects could have on public health and national economies. An important first step in addressing the concern is understanding its economic burden on global society. Ding et al provide a global assessment of the economic burden of physical inactivity released as an online publication in The Lancet. They included not only direct healthcare costs, but also indirect costs of productivity losses, as well as data from low- and middle-income countries as such countries now account for the global majority of non-communicable disease burden [12]. Finally, the authors also attempted to include a “who pays” section, attempting to address on whom – the public sector, private sector, or personal households – these burdens have fallen. The authors follow a clear 9-step algorithm to make their estimations.

The authors used available data from 142 countries, representing 93.2% of the world’s population to estimate direct health-care costs, productivity losses, and disability-adjusted life-years (DALYs). To estimate DALYs the authors specifically focused on cardiovascular disease (coronary heart disease and stroke), as well as type 2 diabetes, breast cancer, and colon cancer. Conservative analyses estimate an international burden for direct healthcare costs of $53.8 billion worldwide in 2013, of which 80% were borne by high-income countries. These direct healthcare costs were distributed over the public sectors which paid $31.2 billion; private sectors, paying $12.9 billion, and out-of-pocket by households, paying $9.7 billion. Productivity losses were estimated to be an additional cost of $13.4 billion worldwide. An estimation of 13.4 million DALYs was made, 75% of which were attributed to low- and middle-income countries.

The authors made the assumption that the unequal burden of DALYs in poorer countries was due to more unmet health needs unaddressed by less developed health systems. Given the decreased DALY burden but increased cost burden in high-income countries, the expectation is that as low- and medium-income countries further develop, their health costs for untreated effects of physical inactivity will also increase. The study is limited by its vastness in subject matter, only focusing on 5 of 22 non-communicable diseases recognized as associated with inactivity, as well as a number of other generalized estimations which the authors openly identify in their article. Nevertheless, it is the first to make estimations on the economic burden of physical inactivity in an effort to promote a global response to the pandemic of health effects caused by physical inactivity. Such estimations are crucial for international organizations to identify cost-effective interventions and policy making in a resource-constrained global economy [13].

Mini Cuts:

A randomized controlled trial of 56 primary care practices found that a 6-month internet behavioral program combined with remote nursing follow-up (emails and phone calls) was more effective than a control of face-to-face dietician program, and equally effective as an internet program and face-to-face nursing visits, with no increase in cost over a 12-month period [14].

Traffic-related air pollution is associated with cardiovascular risk, but the process underlying this association is unknown. Authors of a July 2016 Lancet article follow a 10-year cohort with frequent coronary CTs and carotid artery ultrasound in 6 US metropolitan areas to find a further association between areas of higher ambient traffic-related pollution and acceleration of coronary calcification [15].

Factor Xa inhibitors are becoming an increasingly popular mode of anticoagulation with a broadening number of indications. However, their major drawback is their inability to be reversed in the setting of a major bleed. Authors of a study published in Nature Medicine this week demonstrated the use of a variant coagulation factor, FXaI16L as a reversal agent reducing blood loss in mice with a severe hemostatic challenge while treated with rivaroxaban [16].

Christopher Sonne, MD, is a 2nd year resident at NYU Langone Medical Center

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

Image courtesy of Wikimedia Commons


  1. Healy, Patrick, Amy Chozick. “Hillary Clinton Warns of ‘Moment of Reckoning’ in Speech Accepting Nomination.” New York Times [Philadelphia]. 28 July 2016:
  2. Nelson, Colleen M., Kristina Peterson. “Hackers Target Clinton Campaign, House Democratic Campaign Committee.” The Wall Street Journal. 29 July 2016: 
  3. Poynard T, Calès P, Pasta L, et al. Beta-adrenergic–antagonist drugs in the prevention of gastrointestinal bleeding in patients with cirrhosis and esophageal varices. N Engl J Med 1991;324:1532–1538.5.
  4. Gonzalez R, Zamora J, Gomez-Camarero J, et al. Meta-analysis:combination endoscopic and drug therapy to prevent variceal rebleeding in cirrhosis. Ann Intern Med 2008;149:109–122.
  5. 5. Sersté T, Melot C, Francoz C, et al. Deleterious effects of beta blockers on survival in patients with cirrhosis and refractory ascites. Hepatology 2010;52:1017–1022.7.
  6. 6. Sersté T, Francoz C, Durand F, et al. Beta-blockers cause paracentesis-induced circulatory dysfunction in patients with cirrhosis and refractory ascites: a cross-over study. J Hepatol 2011;55:794–799.8.
  7. Chirapongsathorn, Sakkarin, et al. “Nonselective β-Blockers and Survival in Patients With Cirrhosis and Ascites: A Systematic Review and Meta-Analysis.” Clinical Gastroenterology and Hepatology (2016).
  8. “Fluoroquinolone Antibacterial Drugs for Systemic Use: Drug Safety Communication – Warnings Updated Due to Disabling Side Effects.” 26 July 2016. Web. Accessed 28 July 2016:

9. Lancet risk of dm meds: Udell, Jacob A., et al. “Glucose-lowering drugs or strategies and cardiovascular outcomes in patients with or at risk for type 2 diabetes: a meta-analysis of randomised controlled trials.” The Lancet Diabetes & Endocrinology 3.5 (2015): 356-366.

10. Marso, Steven P., et al. “Supplementary Appendix”: Accessed 29 July 2016.

11. Marso, Steven P., et al. “Liraglutide and cardiovascular outcomes in type 2 diabetes.” New England Journal of Medicine (2016).

12. Abegunde DO, Mathers CD, Adam T, Ortegon M, Strong K.The burden and costs of chronic diseases in low-income andmiddle-income countries. Lancet 2007; 370: 1929–38.

13. Ding, Ding, et al. The economic burden of physical inactivity: a global analysis of major non-communicable diseases. The Lancet. Published Online: 27 July 2016. 

14. Little, Paul, et al. “An internet-based intervention with brief nurse support to manage obesity in primary care (POWeR+): a pragmatic, parallel-group, randomised controlled trial.” The Lancet Diabetes & Endocrinology (2016).

15. Kaufman, Joel D., et al. “Association between air pollution and coronary artery calcification within six metropolitan areas in the USA (the Multi-Ethnic Study of Atherosclerosis and Air Pollution): a longitudinal cohort study.” The Lancet (2016).

16. Thalji, Nabil K., et al. “A rapid pro-hemostatic approach to overcome direct oral anticoagulants.” Nature Medicine (2016).

Primecuts – This Week In The Journals

July 25, 2016

poolBy Vishal Shah, MD

Peer Reviewed

A lone 18-year-old gunman opened fire on the public in the vicinity of the Olympia Shopping mall in Munich, Germany this past Friday July 22nd [1]. He carried a 9mm handgun and roughly 300 rounds of ammunition. Nine victims lost their lives and 35 were wounded [2]. The shooter died of a self-inflicted gunshot wound.

Germany has some of the strictest firearm laws in the world [3]. Those younger than 25 who attempt to buy a gun must have a psychiatric evaluation. Fully automatic weapons are prohibited while semi-automatic firearms are banned unless used for hunting or competitive sports. Authorities believe he obtained the gun illegally from the dark-net, a back-alley encrypted network with restricted access where users may obtain contraband such as drugs and firearms [4]. The serial number of the gun that was used had been scratched off; he did not have a permit. While gun laws did not stop the attacker from carrying out his plans, they may have prevented him from getting access to deadlier weapons.

In related news, an observational study on the effectiveness of gun law reforms was in this week’s JAMA. 

Association between Gun Law Reforms and Intentional Firearm Deaths in Australia, 1979-2013

On April 28th, 1996, a man used 2 semiautomatic rifles to kill 35 people and wound 19 others in the Port Arthur massacre in Australia. After this incident, Australia’s state and federal governments responded by passing uniform gun law reform. This included a ban on semiautomatic rifles and pump-action shotguns and rifles, and also initiated a mandatory buyback program of prohibited firearms.

In this week’s issue of JAMA, there was an observational study using Australian government statistics on deaths caused by firearms from 1979-2013 [5]. In the 18 years prior to the ban, there were 13 mass shootings (defined as 5 or more people killed by gunshot) with a mean annual rate of total firearm deaths of 3.6 (95% CI 3.3-3.9) per 100,000. In the 20 years following the ban, no mass shootings have occurred, with a mean annual rate of total firearm deaths being 1.2 (95% CI 1.0-1.4) per 100,000. The annual rate of total homicide was slightly declining from 1979-1996, and after gun law reform, the decline accelerated.

Limitations of the study include its observational nature, which limit the ability to assign causality. Australia is the first known country to enact wide reaching gun reform. Further policy changes and studies will be needed to provide further evidence of the effects of gun reform. A potential first step would be reversing the “Dickey” Amendment, a rider from the 1996 Omnibus effectively limiting the CDC’s ability to fund federal research on gun control/violence [6].

Initiation Strategies for Renal-Replacement Therapy in the Intensive Care Unit

Renal Replacement Therapy (RRT) is often needed in critically ill patients, however, in non-emergent cases, the ideal time to start RRT remains unclear. A trial published in this week’s NEJM aimed to answer this question by randomizing 620 Intensive Care Unit (ICU) patients with acute kidney injury (AKI) to receive RRT using an early versus delayed strategy [7].

Patients were enrolled if they had Kidney Disease: Improving Global Outcomes (KDIGO) score of 3, and required either mechanical ventilation, or catecholamine infusion. Patients were excluded if they had a potentially life-threatening complication directly related to renal failure.

These patients were then randomized to either receive RRT early in hospital course, versus a delayed strategy, wherein RRT was initiated if patients met pre-specified criteria (pH <7.15, Potassium >6, pulmonary edema leading to hypoxia, oliguria persistent for >72 hours, or blood urea nitrogen (BUN) > 112). Of the 620 patients, 80% had sepsis and 63% had been exposed to a nephrotoxic agent. The form of RRT varied, with 55% of patients receiving intermittent RRT and 45% receiving continuous RRT.

The primary outcome was mortality at 60 days. The early RRT group had a mortality of 48.5% [95% CI 42.6-53.8] and the delayed RRT group had a 60 day mortality of 49.7% [95% CI 43.8-55.0], p 0.79]. Limitations include generalizability given the different forms RRT used and study location was only in France. Adverse events included increased percentage of patients undergoing RRT in the early strategy group (98% versus 51%) and increased catheter-related infection rate (10% versus 5%).

The ideal time to start RRT remains unclear. There is no evidence that starting RRT early improves outcomes, but it was associated with increased risk of infection.

Nonrandomized Intervention Study of Naloxone Co-prescription for Primary Care Patients Receiving Long-Term Opioid Therapy for Pain.

As both opioid prescription and opioid-related overdoses increase, there is growing anxiety about managing these medicines safely in the outpatient setting. In this week’s Annals of Internal Medicine, a study analyzed the benefits of naloxone co-prescription for patients taking chronic opioids [8,9].

This was a nonrandomized intervention study at safety-net primary care clinics, which are a patchwork of individuals, groups, and hospitals that provide primary care to the uninsured, underserved, and other vulnerable populations. The study analyzed 1985 adults receiving long-term opioid therapy for pain. The intervention was training clinicians on prescribing naloxone.

At baseline, patients took an average of 53mg morphine equivalents/day (MME), with 10% of patients taking >400 MME/day. Of the 1985 patients, 38.2% were prescribed naloxone. There was inter-clinic variation in rates of naloxone prescription. Physicians were more likely to prescribe naloxone to patients with a higher risk of overdose, such as those patients on higher doses of opioids, and those with prior ED visits for opioid-related issues. This prescribing pattern reflects the CDC guidelines that were released earlier this year, which advised practitioners to consider offering naloxone to the patients with highest risk of overdose [10].

After 1 year, patients who were prescribed Naloxone had 63% fewer opioid-related ED visits compared with patients who did not have naloxone (Incidence rate ratio (IRR) 0.37 [CI 0.22 – 0.64 p<0.001]). There was no net change of prescription opioid dose by the end of the study (IRR 1.03 [CI 0.91 – 1.27, p 0.61]). No information on actual naloxone usage was collected.

Though there was no clear mortality benefit, a reduction in ED visits is beneficial to both the individual patient and the healthcare system. Therefore naloxone should be considered as an adjunctive therapy, especially for those patients at highest risk of overdosing. However, it is unclear whether the decrease in ED visits was due to naloxone use or from increased awareness of overdose among patients.

State of TeleHealth

Telehealth is the provision of healthcare remotely by means of a variety of telecommunication tools. A review article published in this weeks NEJM gives an overview of the history, current use, limitations, and future directions of telehealth [11].

The early uses of telehealth were to provide care to people who were unable to see a physician in person, such as patients in the military or in rural areas, as well as for acute conditions like cerebrovascular accidents (CVA}. In the past, CVAs were treated in the hospital by a local physician. With the increased use of telemedicine, stroke specialists can provide care remotely, and now the majority of patients with CVA receive specialized care via telemedicine.

Telemedicine is expanding into treatment of chronic conditions as well. Many organizations are beginning to offer low-cost virtual appointments that allow for greater convenience at a lower cost. In fact, Kaiser Permanente predicts that in 2016, it will have more virtual visits than in-person visits.

Among current limitations of telehealth is reimbursement. Twenty-nine states now have telehealth parity laws requiring private insurers to cover telehealth services. If more insurers are to increase reimbursements, more studies will need to perform cost-benefit analysis of particular telehealth programs. Also, many visits are conducted by a physician who has never met with the patient, which can lead to fragmented health care. Additionally, limitations to telehealth include the variability of physician licensing across state lines, the differential access to telecommunications, and the digital divide (which is particularly prominent among patients older than the age of 65).

Despite these limitations, the future of telehealth is promising. The cost of telecommunication is dropping and investments into telehealth are increasing.  In the short term, most of the advances with telehealth will be linked to smartphones. As the number of sophisticated sensors and portable imaging and telecommunications arise, telehealth will expand its reach, enabling more people to receive care. 

Mini cuts:

A 5-year study on early anti-retroviral therapy in patients with HIV-1 was released last week in NEJM [12]. Results suggest that starting ART therapy at the time of diagnosis significantly lowered transmission rates to uninfected partners.

In a study released in May this year the Journal Blood, investigators demonstrated that human neutrophil peptides (HNPs) released from activated neutrophils inhibit the cleavage of von Willebrand factor by ADAMTS13 [13]. This may shed light into the link between inflammation/infection and the onset of microvascular thrombosis in acquired thrombotic thrombocytopenic purpura.

Researchers released a large meta-analysis in JAMA this week comparing clinical outcomes and adverse events associated with anti-diabetic medications in patients with Type II Diabetes [14]. This meta-analysis provides further evidence to continue current standard of care using metformin as a first line agent and utilizing a 2nd agent depending on individual patient characteristics, as no other combination of medications showed significant improvement over one another.

Dr. Vishal Shah is a internal medicine resident at NYU Langone Medical Center

Peer reviewed by David Kudlowitz, MD, chief resident, internal medicine, NYU Langone Medical Center

Image courtesy of Wikimedia Commons



  1. Callimachi R, Eddy M, Jacobs A. Gunman in Munich Kills 9. New York Times. July 22 2016.
  2. Eddy M. Munich gunman portrayed as having planned attack for a year. New York Times. July 24 2016.
  3. BBC. Munich attack: Calls in Germany for tighter gun laws. July 24, 2016.
  4. Noack R. Germany has some of the world’s strictest gun laws, but illegal weapons remain a threat. The Washington Post. July 23 2016.
  5. Chapman S, Alpers P, Jones M. Association Between Gun Law Reforms and Intentional Firearm Deaths in Australia, 1979-2013. JAMA. 2016;316(3):291-299. doi:10.1001/jama.2016.8752.
  6. Jamieson, C. Gun violence research: History of the federal funding freeze. American Psychological Association. February 2013.
  7. Gaudry S, Hajage D, Schortgen F et al. Initiation Strategies for Renal-Replacement Therapy in the Intensive Care Unit. N Engl J Med 2016; 375:122-133. July 14, 2016DOI: 10.1056/NEJMoa1603017
  8. Coffin PO, Behar E, Rowe C et al. Nonrandomized Intervention Study of Naloxone Coprescription for Primary Care Patients Receiving Long-Term Opioid Therapy for Pain. Ann Intern Med. 2016 Jun 28. doi: 10.7326/M15-2771
  9. CDC. Prescription Opioid Overdose Data. CDC. www.cdc.gom/drugoverdose/data/overdose.html 
  10. Dowell, D. Haergerich T. Chou R. CDC Guidelines for Prescribing Opioids for Chronic Pain – United States, 2016. Centers for Disease Control. March 18, 2016.
  11. Dorsey ER and Topol EJ. State of Telehealth. N Engl J Med 2016; 375:154-161July 14, 2016DOI: 10.1056/NEJMra1601705
  12. Cohen MS, Chen YQ, McCauley M et al. Antiretroviral Therapy for the Prevention of HIV-1 Transmission. N Engl J Med. 2016. Epub ahead of print. DOI: 10.1056/NEJMoa1600693
  13. Pillai VG, Bao J, Zander C et al. Human neutrophil peptides inhibit cleavage of von Willebran factor by ADAMTS13: a potential link of inflammation to TTP. Blood. 2016; 128:110-119. doi: 10.1182/blood-2015-12-688747
  14. Palmar SC, Mavridis D, Nicolucci A et al. Comparison of Clinical Outcomes and Adverse Events Associated With Glucose-Lowering Drugs in Patients With Type 2 Diabetes. JAMA. 2016;316(3):313-324. doi:10.1001/jama.2016.9400.

Primecuts – This Week In The Journals

July 18, 2016

france chateauBy Dana Zalkin, MD 

Peer Reviewed

This week the world witnessed a deadly attack in France, a tumultuous coup attempt in Turkey, and the announcement of the Trump-Pence GOP presidential ticket. As crowds gathered to watch the Bastille Day fireworks display in Nice, France, a massacre ensued when a truck plowed through the crowd killing 84 individuals [1].  While the world attempted to come to terms with what had occurred in France, the presumptive US Republican presidential candidate, Donald Trump, officially announced his running mate in the 2016 presidential election: Gov. Mike Pence of Indiana [2].  And as the policies and political climate of this duo were being analyzed around the country, another international crisis erupted as military forces attempted a coup in Turkey [3].

As we mourn the individuals who lost their lives in France, and continue to pray for peace in Turkey and throughout the world, we turn to acknowledge the most recent advances in medical literature this week.

Ablation versus Escalation of Antiarrhythmic Drugs in Patients with Recurrent Ventricular Tachycardia 

Myocardial infarction often results in scarring, which carries a significant risk of ventricular tachycardia (VT) and subsequent death. Implantable cardioverter-defibrillators (ICDs) have been shown to significantly reduce this risk.  Although ICDs are effective at terminating ventricular rhythms, recurrent VT and ICD shocks are not without consequence.  Patients with recurrent ventricular tachycardia, may have impairment in the quality of life as well as increased risk of death, heart failure, and hospitalization.  Anti-arrhythmic drug therapy is often required in these individuals, however if ventricular tachycardia continues to occur despite these medications, options include catheter ablation or escalating drug therapy, both of which have been shown to effectively reduce recurrent arrhythmias.

The Ventricular Tachycardia Ablation versus Escalated Antiarrhythmic Drug Therapy in Ischemic Heart Disease (VANISH) trial published this week in NEJM compared catheter ablation versus escalated anti-arrhythmic drug therapy in patients with ischemic cardiomyopathy and an ICD who had recurrent VT despite first-line anti-arrhythmic therapy [4].  This study was a multi-center, open-label, randomized controlled trial where 259 patients were randomized to either escalation of antiarrhythmic therapy or VT ablation.  At 2 years follow-up, patients who underwent catheter ablation had a 10% absolute reduction in composite outcome of death, VT storm, and appropriate ICD shocks, with the difference largely driven by reductions in VT storm and ICD shocks given no significant difference in mortality.  Adverse events were more common and more frequent in the antiarrhythmic escalation group.  Additionally, subgroup analysis demonstrated that in those patients who have VT while taking an antiarrhythmic drug other than amiodarone or no antiarrhythmic therapy, catheter ablation was not superior to treatment with amiodarone.   Another important effect of this study is the recognition that better antiarrhythmic therapies are ultimately necessary for this group of patients. 

Sex Differences in Physician Salary in US Public Medical Schools 

The gender wage gap has been a conversation piece for quite some time. In 1963 the Equal Pay Act was signed into action, and at that time women earned 59 cents on average for every dollar earned by men [5].  In 2010, women earned 77 cents on average for every dollar earned by men.  Although there have clearly been advances in the wage gap over time, the gap still persists.

A recent study published in JAMA Internal Medicine unfortunately demonstrated that the wage gap does not spare the medical profession [6].  Previous studies aimed at studying salary difference between male and female academic physicians have been limited by self-reporting surveys, small sample sizes, or a focus on one specialty or region.  This new study used public salary data about 10,241 physicians in 12 states from 24 public medical schools and accounted for age, experience, faculty rank, specialty, and scientific authorship. Overall, female physicians (n = 3549) had a lower mean unadjusted salary compared to male physicians (n = 6692) with an absolute difference of $51,315 (95% CI $46,330-$56,301) and a persistent difference after multivariable analysis with an absolute difference of $19,878 (95% CI $15,261-$24,495).  Salary differences were seen across various specialties as well as academic rankings and research productivity.  Interestingly, women were less likely to have received Medicare payments, and in those who were receiving payments, the mean amount received was lower for women ($38,409 vs. $52,320; p < 0.001).

This study represents the largest known study of wage differences between male and female academic physicians to date. Although this study publicized the glaring difference between male and female physician salaries, something must be done now that these differences are recognized.  As Dr. Kim Templeton, the president of American Medical Women’s Association, commented in the recent NY Times article covering this issue, “just having it out there isn’t going to fix the problem” [7]. 

Does Procalcitonin Guidance Reduce the Duration of Antibiotic Treatment in Critically Ill Patients? 

Appropriate antibiotic use is a common challenge in hospitalized patients. Recognizing and treating septic patients with antibiotics is of the utmost importance as sepsis remains a major cause of death in critically ill patients, however excessively long antibiotic courses are detrimental given the risk of increasing antibiotic resistance.  Studies have demonstrated that procalcitonin guidance can decrease the duration of antibiotic treatment for patients with bacterial infections, however the safety of these protocols has not yet been fully established. Another limitation is that many of these studies were performed in countries with high baseline utilization of antibiotics.

A recent study published in Lancet Infectious Disease sought to assess the efficacy and safety of procalcitonin-guided antibiotic treatment in a large set of ICU patients in a health-care system with relatively lower baseline antibiotic use [8].  The Stop Antibiotics on Procalcitonin guidance Study (SAPS) was a prospective, multicenter, randomized, open-label intervention trial performed throughout fifteen ICUs in the Netherlands with 1575 participants.  The procalcitonin-guided group was offered non-binding advice to discontinue antibiotics if procalcitonin concentration decreased by 80% of more of its peak value or to 0.5μg/L or lower.  The standard-of-care group followed local antibiotic protocols.  The median duration of treatment was 5 days in the procalcitonin-guided group and 7 days in the standard-of-care group (absolute difference 2.69, 95% CI 0.65-1.78, p < 0.0001) with a significantly lower daily consumption of antibiotics in the procalcitonin-guided group (p<0.0001).  Mortality at 28 days was 20% in the procalcitonin-guided group vs. 25% in the standard-of-care group (absolute difference 5.4%, 95% CI 1.2-9.5, p=0.0122) in an intention-to-treat analysis, and 20% in the procalcitonin-guided group vs. 27% in the standard-of-care group (absolute difference 6.6%, 95% CI 1.3-11.9, p=0.0154) in a per-protocol analysis.  Overall, procalcitonin appears to be a safe and effective tool to reduce antibiotic treatment duration and utilization in ICU patients with bacterial infections, however it must also be noted that this is a tool to aid and supplement rather than replace physician judgment. 

Does Suppressive Antiretroviral Therapy Prevent Within-Couple HIV Transmission During Periods of Sex Without Condoms? 

HIV transmission amongst heterosexual serodifferent couples has been shown to be significantly reduced in HIV-positive adults randomized to early antiretroviral therapy (ART). However, these studies are limited in that they do not consider transmission rates for anal sex, and they report transmission data in the context of consistent condom use, which also prevents transmission.

The PARTNER (Partners of People on ART- A New Evaluation of the Risks) study was an observational multicenter study of serodifferent couples, including heterosexual and men who have sex with men (MSM) partnerships, that have penetrative sex without condoms in which the HIV-positive partner is taking ART and had a suppressed HIV viral load [9]. 1166 HIV serodifferent couples were enrolled with 888 heterosexual (61.7%) and 340 MSM (38.3%) couples.  Phylogenetic analysis was performed if an HIV-negative partner became infected to determine if the transmission was linked to the HIV-positive index partner.  Couples reported condomless sex acts with a median of 37 times per year, with a total of approximately 22,000 condomless sex acts amongst MSM couples and approximately 36,000 amongst heterosexual couples.  Over a median follow-up period of 1.3 years, 11 HIV-negative partners seroconverted.  However, no phylogenetically linked transmissions occurred resulting in a within-couple HIV transmission rate of zero.  Although more data is needed to determine risk estimates over longer periods of time, the PARTNER study has provided new and important data on the effectiveness of ART as a strategy to prevent HIV transmission through condomless sex.

Mini Cuts 

A randomized, double-blind, phase 3 trial published in NEJM this week compared olanzapine with placebo in patients with no prior chemotherapy who were receiving highly emetogenic chemotherapy [10]. Olanzapine significantly improved nausea-prevention and the complete response rate (no emesis and no use of rescue medication) compared with placebo.

Gastroparesis is a complication seen in patients with diabetes. A recent clinical trial in Gastroenterology compared relamorelin  (a pentapeptide-selective agonist of the ghrelin receptor which speeds gastric emptying) versus placebo [11].  Relamorelin significantly reduced vomiting and improved symptoms of impaired gastric emptying.

A study in JAMA Internal Medicine compared quit attempts in patients receiving pictorial warnings versus text-only warnings on cigarette packs [12].  Pictorial warnings increased intentions to quit, forgoing cigarettes, quit attempts, and successful smoking cessation over the 4 week trial period.

Dr. Dana Zalkin is a 2nd year internal medicine resident at NYU Langone Medical Center

Peer reviewed by Jennifer Mulliken, MD, associate editor, Clinical Correlations; chief resident, NYU Langone Medical Center

Image courtesy of Wikimedia Commons


[1] Higgins, Andrew. “In Nice, a Vibrant Celebration Gives Way to a Trail of Death.” The New York Times. The New York Times, 14 July 2016. Web. 17 July 2016.

[2] Burns, Alexander, and Maggie Haberman. “How Donald Trump Finally Settled on Mike Pence.” The New York Times. The New York Times, 15 July 2016. Web. 17 July 2016.

[3] Arango, Tim. “Turkey Detains Thousands in Military in Bid to Regain Control.” The New York Times. The New York Times, 16 July 2016. Web. 17 July 2016.

[4] Sapp JL, Wells GA, Parkash R, et al. Ventricular Tachycardia Ablation versus Escalation of Antiarrhythmic Drugs. N Engl J Med.2016 Jul 14;375(2):111-21.

[5] “Pay Equity Information.” Pay Equity Information. National Committee on Pay Equity, Sept. 2015. Web. 17 July 2016. <>.

[6] Jena AB, Olenski AR, Blumenthal DM. Sex Differences in Physician Salary in US Public Medical Schools. JAMA Intern Med. 2016 Jul 11.

[7] Louis, Catherine Saint. “Dr. Paid Less: An Old Title Still Fits Female Physicians.” The New York Times. The New York Times, 11 July 2016. Web. 17 July 2016.

[8] de Jong E, van Oers JA, Beishuizen A, et al. Efficacy and safety of procalcitonin guidance in reducing the duration of antibiotic treatment in critically ill patients: a randomised, controlled, open-label trial. Lancet Infect Dis. 2016 Jul;16(7):819-27.

[9] Rodger AJ, Cambiano V, Bruun T, et al. Sexual Activity Without Condoms and Risk of HIV Transmission in Serodifferent Couples When the HIV-Positive Partner Is Using Suppressive Antiretroviral Therapy. JAMA. 2016 Jul 12;316(2):171-81.

[10] Navari RM, Qin R, Ruddy KJ, et al. Olanzapine for the Prevention of Chemotherapy-Induced Nausea and Vomiting. N Engl J Med. 2016 Jul 14;375(2):134-42.

[11] Lembo A, Camilleri M, McCallum R, et al. Relamorelin Reduces Vomiting Frequency and Severity and Accelerates Gastric Emptying in Adults With Diabetic Gastroparesis. Gastroenterology. 2016 Jul;151(1):87-96.

[12] Brewer NT, Hall MG, Noar SM, et al. Effect of Pictorial Cigarette Pack Warnings on Changes in Smoking Behavior: A Randomized Clinical Trial. JAMA Intern Med. 2016 Jul 1;176(7):905-12.

Primecuts – This Week In The Journals

June 28, 2016

Banknotes_(4897267054)By Katherine Nixon, MD

Peer Reviewed 

This week the United Kingdom (UK) had a national vote on whether to stay in or leave the European Union (E.U.). On Thursday June 23rd, the nation voted to leave the E.U. with a win of just 52% [1]. The push for movement out of the E.U. was started when the nation saw a large influx of immigrants, and fears ensued. In the E.U., citizens are allowed to move and live freely within the participating countries. With over 330,000 people who immigrated to the UK in 2015, many of the British citizens felt that their borders were not regulated enough and that they needed to “take control” [1]. The large influx of people was putting strain on their public services such as schools and health care. The supporters of the “Leave” side felt that a “Brexit” as they call it, would give their country more power [1]. Immediate repercussions, including economic downturn, the resignation of British Prime Minister David Cameron, and turmoil between various regions of the UK are being seen. While we continue to watch the future of the newly independent UK evolve, we can take a look at this week’s noteworthy items in the medical literature.

Screening for Colorectal Cancer: US Preventative Services Task Force Recommendation Statement 

Colorectal cancer is a major cause of morbidity and mortality in the United States. In the US, 5% of people at average risk will develop it. Death rates are declining in the US, and our country has one of the highest survival rates from colorectal cancer [2]. This is due, in large part, to screening.

The Unites States Preventative Services Task Force (USPSTF) has published new guidelines, updated from their 2008 recommendations, on screening for colorectal cancer [3]. The USPSTF has compared the data for various screening methods including guaiac-based fecal occult blood test (gFOBT), fecal immunochemical tests (FITs), flexible sigmoidoscopy, colonoscopy, multitargeted stool DNA testing (FIT-DNA), methylated SEPT9 DNA blood test, and computed tomography (CT) colonography.

The updated USPSTF recommends that beginning at age 50, patients should be screened for colorectal cancer, and screening should continue until age 75 (grade A recommendation). Screening in patients age 76-85 should be individualized based on the patient’s history (grade C recommendation). The test used for screening can be chosen based on risks and benefits as well as input from the patient on his/her preference. There are multiple studies showing different levels of effectiveness for each, but there are no empirical data to show that any screening entity is of greater benefit. This is a marked changed from preceding guidelines which recommended screening with specific tests; previously the USPSTF recommended colonoscopy every 10 years, annual FIT, annual high-sensitivity FOBT, or flexible sigmoidoscopy every 5 years combined with high-sensitivity FOBT every 3 years. 

Tenofovir to Prevent Hepatitis B Transmission in Mothers with High Viral Load 

Transmission of the Hepatitis B virus from mothers to their infants is very high (up to 90%) without any treatment. Fortunately, administration of immunoglobulin in addition to the Hepatitis B vaccine is able to decrease the rate of transmission significantly. However, transmission still occurs, most frequently in mothers positive for hepatitis B e antigen (HBeAg) and in mothers with high viral load [4].

A randomized control trial was published in the New England Journal of Medicine examining the use of tenofovir in HBeAg positive pregnant women with an HBV DNA level >200,000 IU/ml to prevent transmission of the virus to their infants [5]. Results show that mothers treated with tenofovir had a statistically significant lower rate of mother-to-child transmission of Hepatitis B as compared to the control group, who received usual care with immunoglobulin and the HBV vaccine only. Number needed to treat (in the intention-to-treat analysis) is 7.7. There were no significant differences between the treatment group and the control group in terms of fetal development or congenital deformity. Clinicians should consider treating their HBeAg-positive pregnant patients that have a high viral load with tenofovir in the future to prevent vertical transmission of the virus to their newborns.

RANK ligand as a potential target for breast cancer prevention in BRCA1-mutation carriers 

Women with the BRCA gene mutation are at a higher risk for breast cancer than the average patient; data has shown that for women with the BRCA1 mutation, the risk for developing breast cancer is 65% by age 70 [6]. Given the very high risk, finding a preventative measure for these patients is of great interest.

Nature Medicine journal published a study in which the drug denosumab, a monoclonal antibody that binds RANK ligand (RANKL), was studied for prevention of breast cancer [7]. By studying the breast tissue of women with and without BRCA1 mutations, the authors of this study first found RANKL and its associated receptor are strongly associated with mammary neoplasm formation. Because of these findings, the authors then attempted to target this ligand for the prevention of cancer cell formation. Genetically-engineered mice subjects deficient in the BRCA1 gene were injected with pre-neoplastic cells and then randomized to receive either an antibody to RANKL vs. control antibody. Results showed a significant delay in tumor formation in mice treated with the RANKL antibody as compared to control. Also in this report, three women were treated with denosumab as part of a pilot study, and histologic examination showed that inhibition of RANKL reduced breast epithelial cell proliferation. The data is encouraging for denosumab as a preventative drug for women at high-risk for breast cancer. Further clinical studies are needed to assess the efficacy and safety in human subjects. 

A randomized controlled trial of gabapentin for chronic low back pain with and without a radiating component 

Low back pain is an issue that affects many; 80% of adults will suffer from back pain at some point in their lifetimes [8]. Clinicians are frequently tasked with trying various treatment options for those affected by the condition.

This study in the journal Pain looked at gabapentin (titrated up to 3600mg daily) for the treatment of chronic low back pain (>/6 months) both with and without associated radiation [9]. They found that after twelve weeks of treatment with gabapentin vs. placebo, pain levels, measured with the Descriptor Differential Scale, decreased in both the gabapentin and control arm of the study without any statistical significance between the two. In addition, there was not a statistically significant difference between the treatment arms in patients with or without radiating pain. Plasma levels of gabapentin had no correlation with pain levels. Finally mood was reported as improved at the end of the 12 weeks in both treatment and control groups with no significant difference between treatment and control arms. In terms of side effects, six symptoms were associated with the gabapentin treatment arm; these included fatigue, dry mouth, difficulties with mental concentration, memory, or visual accommodation, and loss of balance. According to this RCT, gabapentin is not useful in the treatment of chronic low back pain, and because of the side effect profile, the risks may outweigh any benefits for using this drug for the treatment of chronic low back pain, even if there is a radiating component.

Additional Articles:

“Use of Plant-Based Therapies and Menopausal Symptoms. A Systematic Review and Meta-Analysis”

Women going through menopause often look to supplements to help cope with their symptoms. This study examined the efficacy of various interventions in symptoms and found that phytoestrogen supplementations helped with hot flashes and vaginal dryness but not night sweats [10].

“Breast cancer screening with tomosynthesis (3D mammography) with acquired or synthetic 2D mammography compared with 2D mammography alone (STORM-2): a population-based prospective study”

Women are advised to get mammograms to detect breast cancer. This study looks at the benefit vs. risks of 3D vs 2D mammography for detection of breast cancer [11].

“Body-Mass Index in 2.3 Million Adolescents and Cardiovascular Death in Adulthood”

This study found that a BMI in 50th to 74th percentiles, which is currently considered normal, during adolescence is associated with increased cardiovascular and all-cause mortality over the next 40 years [12].

“Protection against malaria at 1 year and immune correlates following PfSPZ vaccination”

This study examines the durability of the malaria vaccine and found that the vaccine is still protective up to at least 59 weeks, and higher doses may be of greater benefit [13]. 

Dr. Katherine Nixon is a 1st year resident at NYU Langone Medical Center

Reviewed by David Kudlowitz, MD, Chief Resident Internal Medicine, NYU Langone Medical Center

Image courtesy of Wikimedia Commons 


  1. Erlanger S. Britain votes to leave E.U.; Cameron plans to step down. The New York Times 23 June 2016. 
  2. Macrae FA. Colorectal Cancer: Epidemiology, risk factors, and protective factors. 
  3. Bibbins-Domingo K. Screening for Colorectal Cancer: US Preventive Services Task Force Recommendation Statement. JAMA. 2016;315(23):2564-2575.
  4. Lee H, Lok AS. Hepatitis B and pregnancy. b pregnancy&selectedTitle=1~150 
  5. Pan CQ, Duan Z, Dai E, Zhang S, Han G, Wang Y, Jiang,H, et al. Tenofovir to Prevent Hepatitis B Transmission in Mothers with High Viral Load. NEJM. 2016;374:2324-2334. 
  6. Antoniou, A, Easton DF, et al. Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case Series unselected for family history: a combined analysis of 22 studies. Am J Hum Genet. 2003 Sep;73(3):709.
  7. Nolan E, Vaillant F, Branstetter D, Pal B, Giner G, Whitehead L, Lindeman, GJ, et al. Rank ligand as a potential target for breast cancer prevention in BRCA1-mutation carriers. Nature Medicine. 2016. 
  8. “Back PainFact Sheet”, NINDS, NIH Publication No. 15-5161.
  9. Atkinson JH, Slater M, Capparelli E, Patel S, Wolfson T, Gamst A, Garfin S, et al. A randomized controlled trial of gabapentin for chronic low back pain with and without a radiating component. Pain. 2016;157(7),1499-1507.
  10. Franco O, et al. Use of Plant-Based Therapies and Menopausal Symptoms. A Systematic Review and Meta-Analysis. JAMA. 2016;315(23):2554-2563.
  11. Bernardi D, et al. Breast cancer screening with tomosynthesis (3D mammography) with acquired or synthetic 2D mammography compared with 2D mammography alone (STORM-2): a population-based prospective study. The Lancet. 2016.
  12. Twig G, et al. Body-Mass Index in 2.3 Million Adolescents and Cardiovascular Death in Adulthood” NEJM. 2016; 374:2430-2440.
  13. Ishizuka A, et al. Protection against malaria at 1 year and immune correlates following PfSPZ vaccination” Nature Medicine. 2016; 22:614-623.


Primecuts – This Week In The Journals

June 20, 2016

Love_vs__HateBy Janice Jang, MD

Peer Reviewed

On Sunday, June 12th a safe haven for the L.G.B.T. community in Orlando bore witness to the deadliest mass shooting in the United States and the worst act of terrorism in our country’s history since 9/11.   The 29-year-old gunman, Omar Mateen, entered the gay nightclub filled with hundreds of people celebrating the club’s weekly Latin Night, and single-handedly turned the scene into a deadly massacre, leaving 49 people dead and 53 wounded [1].  In the aftermath of the shooting, America is once again forced to confront homophobia, terrorism, and gun control, fueling political tensions as we draw closer to the presidential election.  Although we cannot prevent every act of gun violence or terrorism, policymakers can certainly make it harder and rarer by banning civilians from purchasing semi-automatic assault rifles.  The use of such lethal weapons has no place outside of the battlefields in the context of military operations. With that, we turn to some of this week’s published medical advancements that may contribute to reducing the morbidity and mortality in patients throughout our clinical practice.

Long-Acting Opioids Are Associated with Increased Mortality in Patients with Chronic Noncancer Pain

A retrospective cohort study of patients with chronic noncancer pain and no evidence of end-of-life care revealed that prescription of long-acting opioids, when compared with control medications, was associated with a significantly increased risk of all-cause mortality, including deaths from causes other than overdose [2].  Patients were included if they were less than 75 years of age and had a diagnosis of chronic pain in the last 90 days without evidence of cancer, other fatal diseases, or palliative care involvement.  Study drugs were sustained release morphine, controlled release oxycodone, transdermal fentanyl, and methadone.  Control drugs were gabapentin, pregabalin, carbamazepine or low-dose cyclic antidepressants. The end point was death occurring during the follow-up; all out-of-hospital deaths were further classified as unintentional medication overdose, cardiovascular, respiratory, or other injury. Statistical analysis revealed that all-cause mortality was 1.64 times greater in the study group compared to the control group.  There was 1.90 times greater risk of out-of-hospital deaths, 2/3 of the excess deaths were due attributed to causes other than unintentional overdose. In the setting of increasing opioid-related deaths in the U.S, this study reinforces the importance of using non-opioid agents for the treatment of chronic noncancer pain. While non-opioid agents are attractive for this reason, the analgesic effect of nonopioids and the overdose potential of those drugs need further review when determining opioid sparing pain regimens.

Early Aspirin Administration to At-Risk Patients Does not Reduce Risk of ARDS

Acute respiratory distress syndrome, an inflammatory process mediated by alveolar-capillary membrane injury and hypoxemic respiratory failure, remains difficult to treat, with mortality in severe ARDS as high as 40-50%.  Researchers are now focusing on earlier interventions to minimize the risk of developing ARDS or prevent severe consequences in high-risk patients.  Based on prior experimental data showing platelet dysfunction in the development of ARDS [3], early aspirin administration was tested as a preventive and therapeutic strategy.  A double-blind, randomized control trial of 390 patients from 16 medical centers from across the US was conducted.  Inclusion criteria included age 18 years or older, patients admitted through the emergency department with high risk for developing ARDS based on the lung injury prediction score [4].  A loading dose of 325 mg of aspirin was given, followed by 81 mg or placebo within 24 hours of presentation and administered daily for a total of 7 days or until death.  Primary outcome was the development of ARDS by hospital day 7. Secondary outcomes included ventilator-free days, hospital and ICU length of stay, 28-day and 1-year survival, and change in serum biomarkers associated with ARDS.  Among at-risk patients presenting to the ED, the use of aspirin compared with placebo did not reduce the risk of ARDS at 7 days, nor did it have any effects on the secondary clinical outcomes [5]. Despite the increase in knowledge about the pathophysiology of ARDS, preventive strategies and treatment options remain limited. Our best options to date focus on the early recognition of ARDS and implementing mechanical ventilation strategies to prevent lung injury including reliable prediction models and ventilators that help reduce human error in urgent situations.

T2DM Patients Treated with Empagliflozin have Lower Risk of Adverse Cardiovascular Events when Compared with Placebo

More than one-third of patients with type 2 diabetes mellitus (T2DM) develop kidney disease, which is associated with increased mortality.  Despite intensive glycemic control and renin-angiotensin-aldosterone system blockade, T2DM patients remain at increased risk for cardiorenal complications.  In the EMPA-REG OUTCOME trial, researchers investigated the effect of empagliflozin, a selective sodium-glucose cotransporter 2 inhibitor, on cardiovascular outcomes and microvascular outcomes in type 2 diabetics. Empagliflozin reduces serum glucose by increasing urinary glucose excretion.  It has been associated with lowering hemoglobin A1C in T2DM, including those with stage 2 or 3a CKD, reductions in weight and blood pressure, and decreased intraglomerular pressure.  The study examined 7020 patients diagnosed with T2DM with comorbid cardiovascular disease and a glomerular filtration rate of at least 30.  Patients were randomly assigned to either the treatment group (empagliflozin at a dose of 10 mg or 25 mg) or placebo once daily in addition to standard care.  The median duration of treatment was 2.6 years and the median observation time was 3.1 years.  Of note, 80.7% of the patients were taking either an ACE-I or ARB at baseline. Primary outcome was a composite of three major adverse cardiovascular events: first occurrence of death from cardiovascular causes, nonfatal MI, or nonfatal stroke.  There was a significantly lower risk of cardiovascular outcomes in the pooled empagliflozin group than in the placebo group.  Among patients with T2DM who were at high risk for cardiovascular events, the use of empagliflozin was associated with a significantly lower risk of microvascular outcome events (hazard ratio 0.61), lower risk of progression to macroalbuminuria (hazard ratio 0.62) or clinically relevant renal outcomes (i.e. doubling of serum creatinine and initiation of CRRT; hazard ratio 0.54) than placebo when added to standard care.  Equivalent results were seen consistently across the two doses [6].  Though the high cost of the drug may not be affordable for many patients, the cost-benefit analysis of this anti-hyperglycemic medication may be of interest when considering decreased rates of cardiovascular events and worsening nephropathy.

Liraglutide Confers Lower Rate of Adverse Cardiovascular Events than Placebo in T2DM

Liraglutide is an analogue of human glucagon-like peptide 1 (GLP-1), which was approved for treatment of type 2 diabetes mellitus to lower glucose levels.  It has been associated with slight reductions in weight and blood pressure as well as an increase in heart rate.  In 2010, the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial was initiated to evaluate the long-term cardiovascular effects of liraglutide. A multicenter, double-blind placebo-controlled trial was performed on 9340 patients with type 2 diabetes who were at high risk for cardiovascular disease and had a baseline HA1C level of at least 7%.  The majority of the patients had established cardiovascular disease (coronary artery disease, chronic heart failure, cerebrovascular disease, or peripheral vascular disease), chronic kidney disease of stage 3 or higher, or both.  Participants were randomly assigned to receive liraglutide or placebo, and the medial follow-up was 3.8 years in each group.  The median daily dose of liraglutide was 1.78 mg.  The primary composite outcome in the time-to-event analysis was the first occurrence of death from cardiovascular causes, nonfatal MI, or nonfatal stroke.  The liraglutide group was found to have a lower risk of the primary composite outcome (NNT = 66) and lower risk of death from any cause (NNT = 98) than did those in the placebo group.   Regarding the drug’s safety profile, the rate of neoplasms was higher in the group treated with liraglutide when compared to placebo.  Notably, there were 13 patients (0.3%) in the experimental group who developed pancreatic carcinoma and 5 patients (0.1%) in the control group, resulting in a statistically nonsignificant difference with a p-value of 0.06 [7].  But perhaps the most influential deterrent in utilizing this drug is the high cost, which may cause patients to seek alternative antihyperglycemic agents.


The Relationship of Parathyroidectomy and Bisphosphonates with Fracture Risk in Primary Hyperparathyroidism: an Observational Study. 

In Annals this week, an observational retrospective study shows that bisphosphonates are associated with an increase in bone mineral density but not a reduced fracture risk in patients with primary hyperparathyroidism.  Parathyroidectomy was associated with reduced fracture risk regardless of the patient’s candidacy for surgery based on consensus guidelines [8], suggesting that clinicians should consider surgery referrals more favorably for those who meet criteria.

Cardiovascular Events Associated with Use of Tyrosine Kinase Inhibitors (TKI) in Chronic Myeloid Leukoemia

Also in Annals, a retrospective cohort study out of Sweden showed tyrosine kinase inhibitors were associated with an increased risk for arterial and venous vascular events in patients being treated for chronic myeloid leukemia with TKI [9].  Given that the control group was an age-matched and sex-matched sampling from Sweden’s registry of the general citizen population; it is unclear whether this increased risk for adverse cardiovascular events is attributable to TKI or CML alone.

Rituximab and Dose-dense Chemotherapy for Adults with Burkitt’s lymphoma

In a multicenter randomized control trial of 257 adult patients with Burkitt’s lymphoma, the addition of rituximab to the lymphoma malin B chemotherapy regimen (an intensive and complicated regimen consisting of cyclophosphamide, vincristine, prednisone, doxorubicin, high-dose methotrexate, high-dose cytarabine, and intrathecal ara-C) was found to result in improved event-free survival (EFS) and overall survival (OS) when compared with those not given rituximab [10]. Due to the need for early induction data analysis was done on all patients, regardless of the final histological diagnosis; therefore these findings require a reader’s discretion prior to using Rituximab on HIV-neg, histologically confirmed Burkitt’s lymphoma.

Dr.  Janice Jang is a 1st year resident at NYU Langone Medical Center

Peer reviewed by Kerrilynn Carney, MD, chief resident, internal medicine, NYU Langone Medical Center

Image courtesy of Wikimedia Commons 


  1. Alvarez, Lizette, and Richard Perez-Pena. “Praising Isis, Gunman Attacks Gay Nightclub, Leaving 50 Dead in Worst Shooting on U.S. Soil.” New York Times 13 June 2016: A1(L).
  2. Ray WA, Chung CP, Murray KT, et al. Prescription of Long-Acting Opioids and Mortality in Patients with Chronic Noncancer Pain. JAMA. 2016;315(22):2415-2423.
  3. Yadav  H, Kor  DJ.  Platelets in the pathogenesis of acute respiratory distress syndrome. Am J Physiol Lung Cell Mol Physiol. 2015;309(9):L915-L923.
  4. Bauman ZM, Gassner MY, Coughlin MA, et al. Lung Injury Prediction Score Is Useful in Predicting Acute Respiratory Distress Syndrome and Mortality in Surgical Critical Care Patients. Critical Care Research and Practice, vol. 2015, Article ID 157408, 8 pages, 2015.
  5. Kor DJ, Carter, RE, Park PK, et al. Effect of Aspirin on Development of ARDS in At-Risk Patients Presenting to the Emergency Department: The LIPS-A Randomized Clinical Trial.AMA. 2016;315(22):2406-2414.
  6. Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes. NEJM 2016.
  7. Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. NEJM. 2016.
  8. Yeh MW, Zhou H, Adams AL, et al. The relationship of parathyroidectomy and bisphosphonates with fracture risk in primary hyperparathyroidism: an observational study. Ann Intern Med. 2016;164(11):715-723.
  9. Dalen T, Edgren G, Lambe M, et al. Cardiovascular Events Associated with Use of Tyrosine Kinase Inhibitors in Chronic Myeloid Leukoemia: A population-based cohort study. Ann Intern Med. 2016.
  10. Ribrag V, Koscielny, Salles G, et al. Rituximab and dose-dense chemotherapy for adults with Burkitt’s lymphoma: a randomized, controlled, open-label, phase 3 trial. The Lancet. 11-17 June 2016, Vol. 387(10036): 2402-2411.


Primecuts – This Week In The Journals

June 14, 2016

syphillis_or_gonorrhea__-_NARA_-_515076Rina Mauricio, MD

Peer Reviewed 

The presidential primary season ended this week. Former senator Hillary Clinton secured enough delegates to win the Democratic nomination, though her opponent Bernie Sanders has not given up the fight. On the Republican side, Donald Trump is focused on the general election, with Ted Cruz and John Kasich long gone from the race.

This presidential election has already proven to be historic. Hillary Clinton is likely to be the democratic nominee, thus securing her place in history as the first female presidential nominee. And Donald Trump, despite all doubts, has managed to secure the vocal support of those in his party, notably that of Paul Ryan. Should he be the confirmed republican nominee, his bid for president will surely be unforgettable, if not for his politics but for the media hype that will surround his campaign. This upcoming presidential election promises to be lively and historic. With that, we turn to the latest, history-making news in the journals.

USPSTF recommends screening for syphilis in high risk groups every 3 months:

The last recommendations from the US Preventive Services Task Force on syphilis screening in asymptomatic men and nonpregnant women were written in 2004. Given the recent increase in primary and syphilis infection since 2000, new screening guidelines are needed. The USPSTF task force conducted a review of literature from 2004 to 2015 to update syphilis screening guidelines.1

The task force addressed four key questions when establishing their recommendations: effectiveness of screening in reducing syphilis complications and transmission, effectiveness of risk assessment methods, accuracy of diagnostic tests and strategies, and harms related to screening.

The task force identified two thousand potentially relevant articles. However, ultimately, only 9 articles were relevant to the four key questions and subsequently reviewed. Four studies found that routine screening every 3 months in HIV positive men and men who have sex with men (MSM) versus more infrequent screening resulted in a higher detection rate of asymptomatic syphilis. The task force reviewed five studies to determine the accuracy of diagnostic tests, though the authors admit that several of the studies were limited in both method and applicability. Overall, these studies show that initial nontreponemal tests (ie the VDRL or RPR test) should be followed by a confirmatory treponemal antibody detection test (ie the FTA-ABS or TP-PA test). There were no studies identified that answered the effectiveness of risk assessment methods and harms related to screening.

The USPSTF subsequently issued a recommendation to screen for syphilis in asymptomatic, nonpregnant individuals at increased risk for infection. Individuals at increased risk are MSM and HIV positive men and women. The review of the evidence also highlights the overall lack of research on optimal screening methods, risk assessment tools and harms from screening.

New study does not support the use of intensive blood-pressure control in patients with intracerebral hemorrhage:

The ideal blood pressure goal for patients with intracerebral hemorrhage remains controversial. On the one hand, there is a concern for hematoma expansion and subsequent morbidity and mortality in patients with intracerebral hemorrhage and poorly controlled blood pressure. On the other hand, adequate blood pressure is necessary for cerebral perfusion. The investigators of ATACH-2 conducted a trial to determine whether rapid lowering of blood pressure after symptom onset would result in improved morbidity and mortality.2

In an international, multicenter, prospective randomized open-label trial, researchers assigned1000 participants to intensive treatment versus standard treatment. Study investigators defined intensive treatment as hourly systolic blood pressure of 110 to 139 mmHg, versus 140 to 179 mmHg in the standard treatment group. Eligible patients were those 18 years of age or older with a Glasgow coma Scale score of 5 or more and with hematoma measurement of less than 60cm3 on CT scan. Treatment was initiated within 4.5 hours of symptom onset. Intravenous nicardipine was the first medication used, with the dose titrated according to a prespecified protocol. If systolic blood pressure target was not reached, despite maximum nicardipine infusion for 30 minutes, then intravenous labetalol was used. Subsequent medications used were at the discretion of the provider. CT scans were done within 24 hours of treatment initiation and read by individuals blinded to treatment assignments. Investigators defined primary treatment failure as not achieving target systolic blood pressure within 2 hours after randomization. The primary end point was death or moderate to severe disability, as defined by the modified Rankin scale score, at least 10 percentage points lower in the intensive treatment group at 3 month follow-up. An interim analysis showed no difference between the two groups and enrollment was stopped early.

Of the 961 participants with data for analysis of primary outcome, death or disability was observed in 38.7% of patients in the intensive-treatment group versus 37.7% of patients in the standard-treatment group. The percentage of patients with serious treatment-related adverse events was 1.6% in the intensive treatment group and 1.2% in the standard group. Based on these results, the researchers concluded that intensive blood pressure reduction in patients with intracerebral hemorrhage does not provide an incremental benefit.

The ATACH-2 trial results support the previous findings of the INTERACT2 trial, which showed no difference with aggressive versus lenient blood pressure control in patients with intracerebral hemorrhage.  Therefore there is yet to be evidence from randomized trials supporting achieving a goal systolic blood pressure of <140 mmHg within 1-2 hours. Further studies are needed to determine a systolic blood pressure goal in this cohort and whether initiation of treatment sooner than 4.5 hours after symptom onset will have an effect on morbidity and mortality.

Novel score is proposed to determine bleeding risk in patients on anticoagulation with atrial fibrillation:

The HAS-BLED or ORBIT scores are often used in conjunction with the CHADS2-VASC score to determine the risk/benefit of anticoagulation in patients with atrial fibrillation. These bleeding scores, however, have only modest predictive ability. In recent years, researchers have discovered an associated within biomarkers and bleeding risk. A recent study proposes a new biomarker based score, the ABC-bleeding score, to prognosticate risk of major bleeding in these patients.3

Researchers used data from the ARISTOTLE trial for score derivation. The primary goal of the ARISTOTLE trial was to assess efficacy of apixaban versus warfarin in patients with atrial fibrillation and increased stroke risk. Upon enrollment in the ARISTOTLE trial, cardiac troponin-I, troponin-T, GDF-15, cystatin C, NT-proBNP, creatinine, hemoglobin and hematocrit levels were also measured. Major bleeding events were defined as hemoglobin drop of 2g/L or more, transfusion of two or more units of packed red blood cells, fatal bleeding or bleeding in a critical organ. Models were developed using biomarker and clinical data. The strongest predictors of major bleeding were GDF-15, hemoglobin, troponin-T, age and previous bleeding. The concordance index (or c-index), which compares predictive versus actual outcome when using a predictive model, for the ABC-bleeding score was 0.68 (95% CI 0.66-0.70). This is compared to a c-index of 0.61 for the HAS-BLED score (95% CI 0.59-0.63) and 0.65 for the ORBIT score (95% CI 0.62-0.67). These results were then validated externally using data from the RE-LY trial, which compared dabigatran and warfarin in patients with atrial fibrillation and increased stroke risk. The ABC-bleeding score in this cohort resulted in a c-index of 0.71 (95% CI 0.68-0.73).

This study proposes a novel risk assessment tool for bleeding risk while on anticoagulation in patients with atrial fibrillation. Its strength lies in its derivation and validation using data from a cohort in which the score should be used, and it was shown to perform as well as current risk assessment tools. However, the c-index for the ABC score is only incrementally better than the HAS-BLED or ORBIT score. Additionally, the score depends on biomarker levels, some of which (ie GDF-15) are not as readily obtained.

Elsewhere in the journals: 

A higher risk of heart failure was not found in patients on DPP-4 inhibitors:

Multiple, conflicting studies have been published regarding the risk for heart failure hospitalizations in patients on DPP-4 inhibitors. A retrospective study of patients looked at events of hospitalized heart failure in patients on saxagliptin or sitagliptin versus pioglitazone, sulfonylureas and long-acting insulin.4 A higher risk of hospitalized heart failure was not observed in patients taking sitagliptin or saxagliptin. Given the numerous other conflicting studies on this subject, these results will need to be replicated. 

Novel gene is found that correlates with lower non-HDL cholesterol levels:

Researchers in Iceland found a sequence variant that correlated with non-HDL cholesterol levels.5 In a sequence that encodes a subunit of the asiaglycoprotein receptor (ASGPR), a 12-base-pair deletion was associated with lower non-HDL cholesterol levels. ASGPR plays a role in endocytosis of LDL receptors from the cell membrane and therefore postulated that this mutation leads to decreased levels of functional ASGPR, which decreasedremoval of LDL receptors from the cell membrane, leading to lower non-HDL levels.

The prevalence of obesity is on the rise in women:

Researchers determined the prevalence of obesity from 2013-2014 using recent NHANES survey results.6 The prevalence of obesity was 35.0% for men and 40.4% for women during this time period. When comparing this data to prior NHANES survey results from 2005, the prevalence of obesity and class 3 obesity was on the rise for women from 2005-2014, despite adjusting for age, race, education level and smoking status. Further studies are needed to elucidate the cause for this increase.

Dr. Rina Mauricio is a 2nd year resident, Department of Medicine, NYU Langone Medical Center

Peer reviewed by Matthew Dallos, Chief Resident, Medicine,  NYU Langone Medical Center

Image courtesy of Wikimedia Commons 


  1. Force USPST, Bibbins-Domingo K, Grossman DC, et al. Screening for Syphilis Infection in Nonpregnant Adults and Adolescents: US Preventive Services Task Force Recommendation Statement. Jama 2016;315:2321-7.
  2. Qureshi AI, Palesch YY, Barsan WG, et al. Intensive Blood-Pressure Lowering in Patients with Acute Cerebral Hemorrhage. The New England journal of medicine 2016.
  3. Hijazi Z, Oldgren J, Lindback J, et al. The novel biomarker-based ABC (age, biomarkers, clinical history)-bleeding risk score for patients with atrial fibrillation: a derivation and validation study. Lancet 2016.
  4. Toh S, Hampp C, Reichman ME, et al. Risk for Hospitalized Heart Failure Among New Users of Saxagliptin, Sitagliptin, and Other Antihyperglycemic Drugs: A Retrospective Cohort Study. Annals of internal medicine 2016;164:705-14.
  5. Nioi P, Sigurdsson A, Thorleifsson G, et al. Variant ASGR1 Associated with a Reduced Risk of Coronary Artery Disease. The New England journal of medicine 2016;374:2131-41.
  6. Flegal KM, Kruszon-Moran D, Carroll MD, Fryar CD, Ogden CL. Trends in Obesity Among Adults in the United States, 2005 to 2014. Jama 2016;315:2284-91.


Primecuts – This Week In The Journals

June 6, 2016

AliBy Dana Zalkin, MD

Peer Reviewed

This week boxing champion and international legend Muhammad Ali passed away at the age of 74. Ali has been recognized as one the best, if not the best, heavyweight boxer the sport has ever seen [1].  But it wasn’t just his athletic prowess that distinguished him; Ali was known for his religious views, his strong political stances, and his very publicized battle with Parkinson’s disease.  Barack and Michelle Obama summed it up nicely when they remarked on “how fortunate we are that The Greatest chose to grace our time” [2].

Speaking of great athletes of our time, Novak Djokovic beat out Andy Murray to finally clinch the French Open title [3]. With this win, Djokovic became the eighth man in history to complete the career Grand Slam.  Additionally, with this win, Djokovic is in line to potentially achieve a true Grand Slam by winning all four Grand Slam tournaments in the same year.

As we continue to celebrate great athletes, past and present, we turn to celebrate and acknowledge the most recent advances in medical literature this week.

Long Term Follow Up of Fecal Microbiota Transplantation for Severe and/or Complicated Clostridium difficile Infection

Fecal microbiota transplantation (FMT) refers to the practice of taking stool from a healthy individual and introducing it into the gut of a sick individual to cure a specific disease. This treatment method has gained increased favor in treating patients with Clostridium difficile infection (CDI), and in 2013 the American College of Gastroenterology guidelines for managing CDI recommended FMT as an alternative treatment for patients after three or more CDI recurrences [4].  The efficacy of FMT in severe and/or complicated CDI, however, has yet to be investigated.

A multicenter long-term follow-up study published in the Journal of Clinical Gastroenterology looked at the response to FMT for 17 individuals with severe and/or complicated CDI[5]. Severe CDI was defined as the presence of significant abdominal tenderness, albumin <3g/dL or white count >15,000 cells/μL. Complicated CDI was defined as the presence of at least one of the following criteria that could be attributed to CDI: admission to the ICU, hypotension with or without the use of vasopressors, fever, ileus, severe abdominal tenderness, change in mental status, white count >35,000 cells/μL or <2000 cells/μL, serum lactate >2.2mmol/L, and end-organ failure. In terms of symptoms, diarrhea improved in 25% after FMT and resolved entirely in 75% after FMT with mean time to resolution of symptoms 5.7 days. Abdominal pain resolved in 72.7% and improved in 27.3% after FMT.  Primary cure without early CDI recurrence (< 90d) after FMT was seen in 88.2% of patients.  Secondary cure rate (cure after a second FMT) was 94.1%.  Patients tolerated the FMT well without any direct adverse events.  Overall, FMT appears to be a safe and effective therapy for patients with severe and/or complicated CDI, however, given the relatively small sample size of this study, more data is needed prior to recommending the use of FMT as standard therapy for this cohort of patients.

Comparable Outcomes for Critically Ill Patients Cared for by Acute Care Nurse Practitioners and Resident Teams 

In many intensive care units throughout the country, acute care nurse practitioners (ACNPs) and physician assistants (PAs) have been employed in recent years to assist in staffing units that have limited manpower given resident duty hour restrictions. Additionally the number of intensivists is insufficient to meet the increasing demand in critical care units. A recent prospective cohort study sought to investigate long-term outcomes for critically ill patients continually cared for by ACNPs [6].

In this study, there were 9066 admissions to an ICU service with 2366 cared for by ACNPs and 6700 cared for by a resident team. A primary endpoint of 90-day survival was used to compare ACNP teams to resident teams.  A multivariate analysis was conducted and there was no difference found between the ACNP and resident teams in the primary outcome.  Patients admitted to the ACNP service had lower ICU mortality than resident team patients (6.3% versus 11.6%, P = 0.01) however hospital mortality showed no statistical difference.

This study differed from others evaluating advanced care providers in the critical care setting in various ways. The ACNPs cared for patients continuously throughout their ICU stay without fellows or attendings covering at night.  Additionally, this study followed up with patients beyond hospital discharge, further strengthening the evidence that ACNP care is comparable to resident care during hospitalization as well as after discharge.  

Early Initiation of Renal Replacement Therapy May Reduce Mortality in Critically Ill Patients with Acute Kidney Injury 

Acute kidney injury (AKI) is a commonly seen entity in critically ill patients. There have been many advances in the management of AKI, especially in those with life-threatening complications, however it has remained unclear what the best management strategy is for those with AKI who do not yet have those complications.  A randomized single-center clinical trial was published in JAMA this past week evaluating the optimal timing of initiating renal replacement therapy (RRT) in those with severe AKI without life-threatening indications. [7].

231 critically ill patients with AKI Kidney Disease: Improving Global Outcomes (KDIGO) stage 2 and plasma neutrophil gelatinase-associated lipocalin level higher than 150ng/mL were enrolled in the study. The patients were randomly assigned to either undergo early RRT (within 8 hours of diagnosis of KDIGO stage 2) or delayed RRT (within 12 hours of stage 3 AKI or no initiation).  The primary endpoint was 90-day mortality after randomization with various secondary endpoints including 28- and 60-day mortality, evidence of organ dysfunction, recovery of renal function, duration and need for persistent renal support, and ICU and hospital length of stay.  Early initiation of RRT was shown to significantly reduce 90-day mortality compared with delayed initiation of RRT (39.3% versus 54.7% mortality, P=0.03).  The early initiation group also had better renal recovery by day 90 (53.6% versus 38.7%, P=0.02) and shorter RRT duration and length of hospital stay (RRT: 9 days in the early group versus 25 days in the delayed group; P = .04; hospital stay: 51 days in the early group versus 82 days in the delayed group; P < .001). There was no significant difference in need for RRT after day 90, organ dysfunction, or length of ICU stay. Although more data is needed on this topic, this study provides compelling evidence for the early initiation of RRT in critically ill patients with non-life threatening AKI. 

Routine Pre-Procedural Administration of Rectal Indomethacin Reduces Overall Occurrence of Post-ERCP Pancreatitis 

Acute pancreatitis is the most common complication of endoscopic retrograde cholangiopancreatography (ERCP), and the use of rectal NSAIDs in high-risk populations has been shown to decrease the incidence of this complication. A multicenter, single-blinded, randomized controlled trial out of China sought to investigate whether routine pre-procedural administration of rectal indomethacin versus selective post-procedural rectal indomethacin decreases the overall occurrence of post-ERCP pancreatitis [8].  2600 patients were randomized to universal pre-procedure indomethacin or post-procedural indomethacin in high-risk patients.  The primary outcome was overall occurrence of post-ERCP pancreatitis.  Post-ERCP pancreatitis occurred in 6% of high-risk patients in the universal group and 12% of high-risk patients in the risk-stratified group (P=0.0057).  Post-ERCP pancreatitis was less frequent in average-risk patients in the universal group (3%) than in the risk-stratified group (6%) where they did not receive the drug (P=0.0003).  The practice of administering routine pre-procedure rectal indomethacin prior to ERCP decreased the overall occurrence of post-ERCP pancreatitis without an increase in adverse effects.

Mini cuts: 

A randomized clinical trial of patients with emphysema and severe air trapping looked at the effect of usual care (bronchodilators, pulmonary rehabilitation) versus usual care plus bilateral endobronchial coil treatment on exercise tolerance [9].  Although there was a slight improvement in exercise tolerance in those patients who received endobronchial coils, the incidence of major complications was also greater.  More studies are needed to determine the utility of this treatment method.

Treatment with an aromatase inhibitor for 5 years has been the standard of therapy for hormone-receptor-positive early breast cancer in postmenopausal women, however a new study looked at extending treatment to 10 years  [10]. This change in treatment duration was associated with increased rates of disease-free survival and lower incidence of contralateral breast cancer.

Particulate air pollution and traffic-related air pollutants are associated with cardiovascular risk. A prospective 10-year cohort study published in the Lancet sought to determine the underlying disease process contributing to this association [11].  The study demonstrated that increased concentrations of particulate air pollution and traffic-related air pollutants are associated with progression in coronary calcification, and therefore may be contributing to accelerated atherosclerosis.

Dr. Dana Zalkin is a 1st-year resident at NYU Langone Medical Center. 

Peer reviewed by Dr. Amar Parikh, 2nd year internal medicine resident at NYU Langone Medical Center 

Image courtesy of Wikimedia Commons 


[1] Lipsyte, Robert. “Muhammad Ali Dies at 74: Titan of Boxing and the 20th Century.” The New York Times. The New York Times, 03 June 2016. Web. 05 June 2016.

[2] “President Obama’s Statement on Muhammad Ali.” The New York Times. The New York Times, 04 June 2016. Web. 05 June 2016.

[3] Clarey, Christopher. “Novak Djokovic Beats Andy Murray to Claim Elusive French Open Title.” The New York Times. The New York Times, 05 June 2016. Web. 05 June 2016.

[4] Surawicz CM, Brandt LJ, Binion DG, et al. Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections. Am J Gastroenterol. 2013;108:478–498.

[5] Aroniadis OC, Brandt LJ, Greenberg A, Borody T, Kelly CR, Mellow M, Surawicz C, Cagle L, Neshatian L, Stollman N, Giovanelli A, Ray A, Smith R. Long-term Follow-up Study of Fecal Microbiota Transplantation for Severe and/or Complicated Clostridium difficile Infection: A Multicenter Experience. J Clin Gastroenterol. 2016 May-Jun;50(5):398-402. doi: 10.1097/MCG.0000000000000374. PubMed PMID: 26125460.

[6] Landsperger JS, Semler MW, Wang L, Byrne DW, Wheeler AP. Outcomes of Nurse Practitioner-Delivered Critical Care: A Prospective Cohort Study. Chest. 2016 May;149(5):1146-54. doi: 10.1016/j.chest.2015.12.015. Epub 2015 Dec 28. PubMed PMID: 26836900.

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