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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