Primecuts – This Week In The Journals

May 5, 2015

By Matthew Dallos, MD

Peer Reviewed

This Saturday, sports fans were treated to a day of televised glory as American Pharaoh raced across the finish line of the 141st running of the Kentucky Derby in a nail-biter and Floyd Mayweather Jr. defeated Manny Pacquiao in the “Fight of the Century.” While couch potatoes nationwide enjoyed a healthy dose of chips and salsa washed down with a Mint Julep or two, Circulation published another article on the health benefits for the physically active amongst us.

In a single center retrospective cohort study, researchers at Henry Ford Health System studied whether poor cardiorespiratory fitness is a risk factor for the development of atrial fibrillation [1]. Given the significant prevalence of atrial fibrillation in the U.S. and the significant cost associated with treatment, identification of potentially modifiable risk factors is clinically relevant [1].

The researchers assessed a multiracial cohort of 64,561 patients who had undergone exercise treadmill testing as part of the Henry Ford ExercIse Testing (FIT) Project [1]. The authors then looked at the incidence of new atrial fibrillation after a median follow-up of 5.4 years in patients with different levels of cardiorespiratory fitness. Cardiorespiratory fitness was defined by metabolic equivalents of task (METs) on exercise treadmill testing. Multivariable Cox regression modeling adjusted for potential demographic and cormorbid condition confounders as well as use of a range of medications (statins, digoxin, beta-blockers, etc). The authors showed that for each additional MET achieved on treadmill exercise testing, patients had a 7% decreased risk of developing atrial fibrillation (HR 0.93 (0.92-0.94), p<0.001) [1].

The authors concluded that there is an inverse relationship between cardiorespiratory fitness and the risk of developing atrial fibrillation. However, previous studies have also shown that athletes that participate in extreme endurance training may be at increased risk of atrial fibrillation [2]. This data provides another reason to get off the couch and stay physically active.

In other medical literature this week, researchers published results of a Phase 3 trial of a recombinant subunit vaccine for herpes zoster in the New England Journal of Medicine[3]. This randomized, multi-center placebo-controlled study, funded by GlaxoSmithKline, called the Zoster Efficacy Study in Adults 50 Years of Age or Older (ZOE-50), tested the efficacy of a recombinant VZV glycoprotein E vaccine versus placebo in reducing the risk of herpes zoster in older patients.

The currently available Zostavax vaccine, which is a live-attenuated vaccine for herpes zoster, can significantly decrease the risk of developing herpes zoster (51% efficacy) [3]. However use of this live-attenuated vaccine is contraindicated in immunosuppressed patients (who are at higher risk of developing herpes zoster), making development of alternative vaccines essential to reducing the burden of disease.

The ZOE-50 Trial tests a recombinant vaccine that does not have the risk of viral replication associated with live-attenuated vaccines in immunosuppressed patients. In the study, 7698 patients received the recombinant vaccine versus 7713 patients who received a placebo [3]. Vaccine efficacy was 97.2% (95% CI 93.7 to 99.0) at a mean follow-up of 3.2 years with a number needed to treat to prevent shingles of 114 [3].

Subgroup analysis stratified patients by age group (50-59 years, 60-69 years and >70 years). Previous studies have shown that the Zostavax has decreased efficacy with age (69.8% in patients 50-59 and 37.6% in patients >70). However the recombinant vaccine used in the ZOE-50 Trial showed no decrease in efficacy with age (96.6% efficacy in 50-59 age group versus 97.9% in the >70 age group) [3]. Adverse events were of mild to moderate intensity in the study and included pain and swelling at the injection site as well as myalgias, headache, fever and gastrointestinal symptoms.

This study presents the development of a new vaccine for herpes zoster that may be better suited for immunosuppressed patients, although this was not specifically assessed in the current study. In addition, the data published in this study offers the potential of a vaccine that is more effective than the Zostavax (especially in those over 70). However since this study was not a direct comparison between Zostavax and the recombinant vaccine, conclusions regarding superiority between the vaccines cannot be made.

Also new this week, the Journal of the American Medical Association (JAMA), published a study on the use of retrievable inferior vena cava (IVC) filters in addition to anticoagulation versus anticoagulation alone in the treatment of patients with acute venous thromboembolism (VTE) [4].

Given the increasing use of IVC filters in patients with VTE and the limited data on whether these devices provide additional protection against pulmonary embolism when used in combination with anticoagulation, the authors designed a randomized, open-label, blinded endpoint trial to assess their efficacy.

In this study, 399 patients with confirmed acute pulmonary embolism and lower-limb vein thrombosis were randomized to retrievable IVC filter plus 6 months of anticoagulation versus 6 months of anticoagulation alone. IVC filters were removed at 3 months. The primary outcome of this study was fatal or symptomatic pulmonary embolism at 3 months. At 3 months, 6 patients in the IVC filter group had recurrent pulmonary embolisms versus 3 patients in the anticoagulation alone group [4].

The authors conclude that there is no role for retrievable IVC filters in addition to anticoagulation after an acute pulmonary embolism. While this study provides evidence to support judicious use of IVC filters in patients with pulmonary embolisms and lower limb thrombosis, particular subgroups of patient with pulmonary embolisms may still benefit from IVC filter placement in addition to anticoagulation.

In another article from JAMA, researchers studied Emergency Room treatment of opioid dependence versus outpatient referrals alone [5].

Efforts to develop more effective treatment strategies are essential to combat the increasing prevalence of opioid dependence and the association of opioid dependence with other medical comorbities. Buprenorphine/naloxone offers a pharmacological intervention to treat craving and withdrawal that is frequently used by addiction treatment programs. Since emergency department physicians frequently see opioid dependent patients presenting with other medical complaints, they are in a unique position to address opioid dependence. Previous interventions have primarily been limited to referral to addiction treatment services. In this study, the authors compare ED-initiated treatment with buprenorphine/naloxone plus a brief negotiation interview and outpatient referral to a brief negotiation interview and outpatient referral to outpatient referral alone.

329 patients were randomized to the different interventions [5]. The primary endpoint was enrollment in formal addiction treatment at 30 days after randomization [5]. The results showed that 78% (CI 70-85%) of patients in the buprenorphine/naloxone group versus 45% (CI 36-54%) in the brief negotiation group versus 37% (CI 28%-47%) in the referral group were participating in a treatment program at 30 days [4]. The number needed to treat between the buprenorphine/naloxone group versus the outpatient referral alone was 2.4. This data supports an ED-initiated pharmacologic treatment approach to opioid dependence in conjunction with appropriate outpatient followup.

Other interesting articles from the week:

The NEJM published 2 articles that tested new therapies for EGFR Inhibitor-Resistant Non-Small Cell Lung Cancer (NSCLC). The first evaluated AZD9291, an irreversible EGFR tyrosine kinase inhibitor that has previously shown pre-clinical efficacy against the common T790M resistance mutation [6]. Tumor response rate was 61% (CI 52-70%) in patients with confirmed EGFR T790M mutations and overall survival was 9.6 months in patients with EGFR T790M mutations versus 2.8 months without the mutation [6]. The second study, published in the same issue of the NEJM, studied raciletinib, another EGFR T790M specific inhibitor [7]. Response rate in T790M positive patients was 59% (CI 45-73%) in this study [7].

Finally a new study in Nature Medicine identified pancreatic NMDA receptors as potential targets in diabetes mellitus [8]. The authors found that in vitro and in vivo inhibition of pancreatic NMDA receptors with dextromethorphan enhanced glucose tolerance and increased serum insulin levels [8].

Dr. Matthew Dallos is a 3rd year resident at NYU Langone Medical Center

Peer reviewed by Gregory Katz, Medicine, NYU Langone Medical Center

Image courtesy of Wikimedia Commons


1. Qureshi W, Zaid A, et al. Cardiorespiratory Fitness and Risk of Incident Atrial Fibrillation: Results from the Henry Ford ExercIse Testing (FIT) Project. Circulation (2015): CIRCULATIONAHA-114.

2. Heidbuchel H, Anne W, Willems R, Adriaenssens B, Van de WF, Ector H. Endurance sports is a risk factor for atrial fibrillation after ablation for atrial flutter. Int J Cardiol (2006) 107:67-72.

3. Lal H, Cunningham A, et al. Efficacy of an Adjuvanted Herpes Zoster Subunit Vaccine in Older Adults. NEJM (2015) Apr 28; [e-pub].

4. Mismetti P, Laporte S, et al. Effect of a Retrievable Inferior Vena Cava Filter Plus Anticoagulation vs Anticoagulation Alone on Risk of Recurrent Pulmonary Embolism: A Randomized Control Trial. JAMA. 2015. 313(16):1627-1635.

5. D’Onofrio G, O’Connor P, et al. Emergency Department-Initiated Buprenorphine/Naloxone Treatment for Opioid Dependence: A Randomized Control Trial. JAMA. 2015. 313(16):1636-1644.

6. Janne P, Chih-Hsin Yang J et al. AZD9291 in EGFR Inhibitor-Resistant Non-Small-Cell Lung Cancer. 2015. 372:1689-99.

7. Sequist L, Soria J, et al. Rociletinib in EGFR-Mutated Non-Small-Cell Lung Cancer. NEJM. 2015;372:1700-1709.

8. Marquard J, Otter S, et al. Characterization of pancreatic NMDA receptors as possible drug targets for diabetes treatment. Nature Medicine. 2015. 21:363-372.