Primecuts – This Week In The Journals

January 11, 2016

vitamin-DBy Matthew McNeill, MD

Peer Reviewed

The holidays have ended, the trees and tinsel have been taken down, and winter has officially arrived in New York City. Unseasonably warm weather (from the second warmest year in history [[1]]) up to this point has kept the influenza virus as a sporadically diagnosed condition in New York and much of the United States. The advent of cooler air, lower humidity, enclosed spaces, runny noses, and decreased Vitamin D are sure to change that in coming weeks [[2]].

So get your vaccine and keep scrubbing those hands!

Our Primecuts this week follows the traditional wedding adage of “something borrowed, something blue, something old, something new.” Whether borrowing traditionally recreational marijuana therapies for medical purposes, decreasing incidence of code blues in managing atrial fibrillation in sepsis, updating old guidelines for venous thromboembolic disease, or publishing phase 3 trials on new treatments for all hepatitis C genotypes, we have you covered.

Oral Cannabinoids As Add-On Therapy May Safely Reduce Seizure Frequency in Treatment-Resistant Epilepsy

With the upcoming legalization of oral medical marijuana in New York State, it is important for providers to know the efficacy and safety of its use in specific severe and debilitating conditions [[3]]. One eligible diagnosis, epilepsy, was examined in an open-label trial recently published in the Lancet Neurology. Specifically looking at children and young adults with severe, intractable, childhood-onset, treatment-resistant epilepsy, concomitantly with baseline antiepileptic drugs therapy, oral cannabidiol was titrated up weekly by 2-5mg/kg to max doses of 25mg/kg or 50mg/kg daily [[4]]. One hundred thirty-seven subjects were analyzed for efficacy and 162 subjects were analyzed for safety profile. This study was open-label and uncontrolled, so it is limited by placebo effect, however over the 12 weeks, baseline median monthly motor seizure frequency decreased from 30.0 to 15.8. The main adverse effects were somnolence (25%), decreased appetite (19%), diarrhea (19%), and fatigue (13%). Despite the rate of adverse effects, over the course of 12 weeks, only 3% of patients stopped the cannabidiol treatment secondary to adverse effects. Although additional randomized control trials confirming these findings are needed, initial results suggest a benefit of marijuana for a difficult-to-manage medical condition. Broadened legalization and acceptance of medical marijuana will continue to provide opportunities for providers to determine benefit in other challenging conditions.

Intravenous Beta-blockers Provide Superior Clinical Outcomes for Treatment of Atrial Fibrillation in Sepsis

Affecting upwards of 25% of hospitalized patients with sepsis, atrial fibrillation is associated with poor morbidity and mortality outcomes including increased risks of stroke, heart failure, and death [[5]]. Although algorithms suggest direct current cardioversion for management of atrial fibrillation in decompensating patients, this is often ineffective or not indicated in septic patients. However, management with traditional intravenous rate or rhythm controlling agents such as beta blockers, calcium-channel blockers, digoxin, or amiodarone can present challenges in the form of worsening hypotension and organ toxicity. A retrospective cohort study published this week in Chest examined management of 39,693 patients with atrial fibrillation in sepsis from 2010-2013 [[6]]. Calcium channel blockers were the initial treatment for 36%, beta blockers for 28%, digoxin for 20%, and amiodarone for 16%. In propensity-matched patients, beta blocker use was associated with improved hospital mortality as compared to calcium channel blockers (18.3% v. 20.0%, n=18,720, RR 0.92), digoxin (20.5% v. 25.7%, n=13,994, RR 0.79), or amiodarone (27% v. 42%, n= 5,388, RR 0.65), without significant effect modification in relevant subgroups including atrial fibrillation onset (pre-existing or new), presence of shock, heat failure, and hypertension history. The study did not examine adverse outcomes associated with the various treatments, only using hospital mortality as the isolated end point. Although hospital mortality was lowest with beta blockers in this retrospective study, a prospective randomized control trial would be the ideal way to determine the best practice for managing atrial fibrillation in sepsis. 

American College of Chest Physicians Recommend Non-Vitamin K Antagonists Oral Anticoagulants As First Line for Treatment of VTE

In the first update since 2012, the American College of Chest Physicians released the 10th edition of Antithrombotic Therapy for VTE Disease: CHEST Guideline based on several new research studies [[7]]. Among the 53 updated recommendations, perhaps the most clinically significant is the Grade 2B recommendation for use of non-vitamin K antagonist oral anticoagulants (NOACs) such as dabigatran (pradaxa), rivaroxaban (xarelto), apixaban (eliquis), edoxaban (savaysa) over VKA therapy (warfarin/coumadin) in patients with lower extremity deep venous thrombosis or pulmonary embolism in absence of cancer. The guideline also recommends daily aspirin use to prevent recurrent venous thromboembolism in patients deciding to stop systemic anticoagulants (Grade 2C). A change from the previous guideline is the suggestion to not use compression stockings to prevent post-thrombotic syndrome (Grade 2B). Finally, in an often grey area of clinical judgment, the new guideline advises not to treat subsegmental (without involvement of more proximal pulmonary arteries) pulmonary embolisms in absence of proximal lower extremity deep venous thrombosis or increased risk of recurrent venous thromboembolism (Grade 2C). In terms of clinical applications, the new guideline advises NOACs for non-malignant DVT/PEs, aspirin as an inferior yet alternative prevention of VTE, stopping use of compression stockings for post-thrombotic syndrome, and holding off on treatment of isolated low-risk subsegmental PEs.

Phase 3 Trials Show HCV Sustained Virologic Response with Sofosbuvir and Velpatasvir in Patients with Decompensated Cirrhosis In All Genotypes

Adding to the seemingly weekly breakthroughs in treatment of hepatitis C, a new multi-center phase 3 trial (co-authored by NYU’s own Lewis Teperman, M.D.) [[8]] published this week in the New England Journal of Medicine demonstrated that treatment with sofosbuvir–velpatasvir with or without ribavirin for 12 weeks and with sofosbuvir–velpatasvir for 24 weeks resulted in high rates of sustained virologic response in patients with HCV infection and decompensated cirrhosis in all genotypes. This is the culmination of a series of Phase 3 trials (ASTRAL) investigating a once-daily fixed dose combination of nucleotide analog polymerase inhibitor sofosbuvir with velpatasvir, an investigational pangenotypic NS5A inhibitor. Currently, the only FDA approved single table regiment for HCV genotype 1 is ledipasvir/sofosbuvir (Harvoni). Rates of sustained virologic response in HCV genotype 1a/b with sofosbuvir–velpatasvir for 12 weeks (88%/89%) and sofosbuvir–velpatasvir-ribavrin for 12 weeks (94%/100%) were similar to previous trials. Rates of sustained virologic response across all genotypes were 83% with 12 weeks of sofosbuvir–velpatasvir, 94% with 12 weeks of sofosbuvir–velpatasvir and ribavirin, and 86% with 24 weeks of sofosbuvir–velpatasvir. Significantly, there was a sustained virologic response rate of 85% in patients with HCV genotype 3 who received sofosbuvir–velpatasvir and ribavirin for 12 weeks, besting previous best rates of 71% in combination treatment with other direct-acting antiviral agents. With the results of this study, Gilead has applied for FDA priority review designation for the use of sofosbuvir–velpatasvir to treat all HCV genotypes [[9]].


Other interesting health related commentary and events of the week…

President Obama to use executive action to expand gun background checks, enhance government ability to enforce gun safety, expand access to mental health services by $500 million, and ease regulation on research into gun safety [[10]]. 

A look at two different approaches to Medicaid expansion under the Affordable Care Act in Arkansas and Kentucky found great improvements in access and care compared to states that did not expand Medicaid. Data showed vast improvement in rates of insurance for low-income adults, increased regular checkups for chronic conditions, decreased skipped medications due to cost [[11]].

Cancer death rates in the United States are down 23% since 1991, according to a report by the American Cancer Society [[12]]. Decreased death rates in four prevalent cancers (breast, colon, lung, and prostate) were major drivers of the improvement, which can be credited to earlier detection, treatment advances, and decreased tobacco use.

Dr. Matthew McNeill, Internal Medicine, NYU Langone Medical Center

Peer reviewed by David Kudlowitz, MD, Internal Medicine, NYU Langone Medical Center

Image courtesy of Wikimedia Commons


[[1]] Gardner, T. NOAA Says 2015 Was Second Hottest Year On Record In U.S. Huffington Post. Published January 7, 2016.§ion=science

[[2]] Centers for Disease Control and Prevention. Flu Activity & Surveillance. Published January 2016. Accessed January 7, 2016.

[[3]] New York State Government. New York State Medical Marijuana Program. Published January 2016. Accessed January 7, 2016.

[[4]] Devinsky O, Marsh E, Friedman, D et al. Cannabidiol in patients with treatment-resistant epilepsy: an open-label intervention trial. Lancet Neurology. December 23, 2015; in press online.

[[5]] Walkey AJ, Greiner MA, Heckbert SR, et al. Atrial fibrillation among Medicare beneficiaries hospitalized with sepsis: incidence and risk factors. Am Heart J. 2013;165(6):949-955.e3.

[[6]] Walkey AJ, Evans S, Winter M. et al. Practice Patterns and Outcomes of Treatments for Atrial Fibrillation During Sepsis : A Propensity-Matched Cohort Study Treatments of Atrial Fibrillation During Sepsis. Chest. 2016;149(1):74-83.

[[7]] Kearon C, Akl E, Ornelas J, et al. Antithrombotic Therapy for VTE Disease: CHEST Guideline. Chest. 2016. Available online. doi:10.1016/j.chest.2015.11.026 ith Bzowej,ws. The White House.ated low-risk subsegmental PEs.drome, and on-malignant DVT/PEs,tal mortality as the isolated end

[[8]] Curry MP, O’Leary JG, Bzowej N, et al. Sofosbuvir and Velpatasvir for HCV in Patients with Decompensated Cirrhosis. N Engl J Med 2015; 373:2618-2628.

[[9]] Gilead Sciences. Gilead Announces U.S. FDA Priority Review Designation for Sofosbuvir/Velpatasvir for Treatment of All Genotypes of Chronic Hepatitis C Infection. Business Wire. Published January 4,2016.

[[10]] The White House. Fact Sheet: New Executive Actions to Reduce Gun Violence and Make Our Communities. Whitehouse.Gov. Published January 4, 2016.

[[11]] Goodnough, A. Better Health Care Access in Kentucky and Arkansas, Study Says. New York Times. Published January 5, 2016.

[[12]] HealthDay News. Cancer Death Rates Down 23 Percent Since 199: Study. MedlinePlus. Published January 7, 2016.