Weekly Evidence Updates 7.2.18

Association of Metformin Use With Risk of Lactic Acidosis Across the Range of Kidney Function (JAMA 7/2018)

Metformin has long been associated with a risk of lactic acidosis, leading to cautious prescribing practices. This has led to curtailed use in individuals with decreased renal function (ie. CKD or patients with CHF). Most of this concern arose from a cousin of metformin, phenphormin- which was removed from the US market in 1978. More recent data has shown significant benefit to metformin use amongst these patient populations, ultimately leading to changes in FDA guidelines surrounding metformin prescribing (Crowley MJ, Diamantidis CJ, McDuffie JR, Cameron CB, Stanifer JW, Mock CK, et al. Clinical Outcomes of Metformin Use in Populations With Chronic Kidney Disease, Congestive Heart Failure, or Chronic Liver Disease: A Systematic Review. Ann Intern Med. 2017;166:191–200. doi: 10.7326/M16-1901). Due to these changes, the Authors of the above article aimed to evaluate metformin use in 75,000 patients with varying stages of CKD. Patients with ESRD or an eGFR < 15 mL/min were excluded. The primary outcome was hospitalization for acidosis other than DKA. Metformin use was associated with a risk of acidosis (HR 2.01) at an eGFR < 30 mL/min. Acidosis was also more common amongst patients with CKD either on or off metformin- an important point the authors mention as a potential confounder in prior studies. Interestingly, sulfonylurea had a similar association with acidosis overall compared to metformin.

Take Home: Metformin use appears safe down to an eGFR of 30 mL/min. It should not be initiated at an eGFR below 45 mL/min. This trial confirmed current FDA labeling which recommends against metformin use with an eGFR < 30 mL/min. New prescribing guidelines focus on the eGFR, and no longer consider a creatinine > 1.5 in men or 1.4 in women as contraindications to metformin use.

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Aldosterone Antagonist Therapy and Mortality in Patients With ST-Segment Elevation Myocardial Infarction Without Heart Failure (JAMA 7/2018)

The mineralocorticoid receptor antagonists (MRA), specifically the aldosterone antagonists eplerenone and spironolactone have been cornerstones of therapy for congestive heart failure since the publishing of the RALES trial (NEJM, 1999) that demonstrated a decreased mortality in patients with NYHA class III-IV HF and an EF < 35%. Since then, further studies have looked at the role of MRA therapy in the ACS setting. Specifically, the EPHESUS trial (NEJM,2003) showed a reduction in morbidity and mortality in patients post-ACS for patients with an EF < 40% and clinical heart failure, or diabetes. The authors of this meta-analysis of 10 studies (4,147 patients) evaluated the role of MRA therapy in STEMI patients with an LVEF > 40% and without clinical heart failure. Most patients included received MRA therapy within 24 hours post-STEMI, and had a follow up period of 6-12 months. The authors found MRA therapy reduced mortality (OR 0.62 (0.42-0.91)) compared to controls. MRA therapy was also associated with a small but significant increase in LVEF (mean difference 1.58%, p=0.03, I2=99). There was no reported difference in the rate of recurrent MI, CHF, or ventricular arrhythmias. Adverse effects included elevated potassium levels.

Take home: Aldosterone Antagonists may improve mortality in patients following STEMI who do not have an LVEF < 40% or clinical heart failure. Ongoing RCT’s are currently being conducted further assess the role of Aldosterone antagonists in post-STEMI care.

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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.