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).