Weekly Evidence Updates 6.25.18

Combined analysis of Asthma Safety Trials of Long-Acting 2- Agonists (NEJM 6/2018)

Controversy has surrounded whether or not long acting beta agonist (LABA) medications are safe in patients with asthma, with some trials showing increased mortality with their use, and others demonstrating that they are safe to use when combined with an inhaled corticosteroid (ICS). The study presented above is the result of a pooled, prospective analysis of a randomized controlled trial assessing the non-inferiority of LABA+ICS vs ICS alone. The authors looked at asthma related intubation and death as a primary outcome. Secondary outcomes included serious asthma related events (which added in hospitalizations), and asthma exacerbations. The authors found no difference in the rate of serious asthma related events, but fewer asthma exacerbations with the LABA+ICS combination. This data arrives on the heels of 2 other recently published studies looking at the use of budesonide/formoterol as both maintenance and reliever therapy (SMART therapy: Single Maintenance And Reliever Therapy) for patients with mild asthma (O’byrne, Paul M., et al. "Inhaled combined budesonide–formoterol as needed in mild asthma." New England Journal of Medicine 378.20 (2018): 1865-1876.). It is worth noting that industry was heavily involved in the above study as this safety trial was mandated by the FDA.

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Take home: LABA+ICS appears safe for use in patients with asthma (current guidelines already use for moderate persistent asthma and more severe asthmatics). Their use may be worthwhile in patients with mild persistent asthma as single agent reliever therapy. Their use as a first line maintenance therapy with overall less corticosteroid exposure compared to ICS maintenance has yet to be studied.

Hydrocortisone plus Fludrocortisone for Adults with Septic Shock (APROCCHSS Trial) (NEJM 3/2018)

Steroids have been used in septic shock for some time. Some trials demonstrated a mortality benefit (ie. Annane D, Sébille V, Charpentier C, et al. Effect of Treatment With Low Doses of Hydrocortisone and Fludrocortisone on Mortality in Patients With Septic Shock. JAMA. 2002), while others have not demonstrated this such as the ADRENAL (nejm 2018), HYPRESS (JAMA 2016), and CORTICUS (nejm 2008). The effects of steroids in shock are not entirely clear, but are thought to augment vascular tone in response to vasopressors. The APROCCHSS trial randomized patients to hydrocortisone+fludrocortisone (50 mg Q 6 hours and 50 mcq QD, respectively) vs. drotrecogin alfa (aPC- now off the market), a combination of all three drugs, or placebo. These were given for 7 days in patients with evidence of indisputable or probable septic shock (documented infection+SOFA score 3-4 in at least 2 organ systems for at least 6 hours, and vasopressors for ≥ 6 hours). The Authors found that the combination of hydrocortisone plus fludrocortisone reduced all cause mortality at day 90, at discharge from the ICU or hospital, and at day 180. Mortality overall was high (43% in treatment arm, and 49% in control arm at day 90), speaking to the high mortality seen in septic shock. Significant adverse events were not seen, other than more hyperglycemia in the steroid group.

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Take Home: For patients with septic shock who have been on vasopressor therapy for at least 6 hours, addition of hydrocortisone and fludrocortisone improves overall mortality at 90 days and hospital discharge.