By Van Selby, MD

Assistant Professor of Medicine, University of California, San Francisco Cardiology Division, Advanced Heart Failure Section

Dr. Selby reports no financial relationships relevant to this field of study.

SYNOPSIS: When studying cardiogenic shock after acute myocardial infarction, these investigators found using epinephrine compared to norepinephrine produced similar effects on blood pressure and cardiac index, but resulted in a higher incidence of refractory cardiogenic shock.

SOURCE: Levy B, Clere-Jehl R, Legras A, et al. Epinephrine versus norepinephrine for cardiogenic shock after acute myocardial infarction. J Am Coll Cardiol 2018;72:173-182.

Among patients with acute myocardial infarction (AMI), the development of cardiogenic shock (CS) is associated with high mortality. Vasopressors are used to raise blood pressure and maintain end-organ perfusion, with epinephrine and norepinephrine the two most commonly used agents. However, data directly comparing the effects of epinephrine and norepinephrine in CS are lacking.

In a multicenter, prospective, double-blind study, Levy et al randomized 57 patients with CS after AMI to epinephrine vs. norepinephrine. All patients underwent successful revascularization by percutaneous coronary intervention (PCI) and met pre-specified criteria for CS (hypotension, cardiac index < 2.2 L/min/m2, wedge pressure > 15 mmHg, and left ventricular ejection fraction < 40% before inotropic support). In both groups, the study drug was titrated for a target mean arterial pressure (MAP) of 65-70 mmHg. The primary efficacy outcome was the change in cardiac index at 72 hours. The primary safety endpoint was the incidence of refractory CS, which the authors defined as CS with major cardiac dysfunction according to echocardiography, elevated serum lactate level, and acute deterioration of end-organ function as well as sustained hypotension.

For the primary outcome, there was no significant difference in cardiac index between the two groups (P = 0.43), although cardiac index was transiently higher in the epinephrine group at hours two and four. Similarly, there was no significant difference in mean arterial pressure (P = 0.80).

The incidence of refractory CS was significantly higher in the epinephrine group compared to the norepinephrine group (37% vs. 7%; P = 0.008), leading to early termination of the study. Epinephrine also was associated with significantly higher increases in heart rate (P < 0.0001), cardiac double product (P = 0.0002), and lactic acidosis (P < 0.0001). Death at 60 days occurred in 52% of patients in the epinephrine group and 37% of patients in the norepinephrine group (P = 0.25). Epinephrine was associated with a trend toward increased death at day seven and a significantly higher risk of death or need for extracorporeal circulatory support at day seven (P = 0.031).

The authors concluded that among patients with CS secondary to AMI, epinephrine use compared to norepinephrine use is associated with similar effects on cardiac index and arterial pressure, with a higher incidence of refractory shock.

COMMENTARY

Data from well-conducted, randomized trials in CS are scarce, and multiple expert panels have stressed the need for more clinical trials to inform treatment decisions. In one of the only previous randomized trials comparing two vasopressors for shock, dopamine was associated with higher mortality compared to norepinephrine in the subgroup of patients with CS. Although small, the Levy et al study is important because it directly compares the two most commonly used vasopressors.

The observed hemodynamic differences between the two agents mostly make sense. Both drugs successfully raised and maintained arterial pressures. However, it seems epinephrine does this at a higher metabolic cost. Epinephrine significantly increases heart rate and the cardiac double product (meaning higher myocardial oxygen consumption). These changes are likely related to the higher ß activity with epinephrine and may be particularly harmful in CS patients with pre-treatment tachycardia, ischemia, or increased risk of arrhythmias.

Although the study was relatively small and not powered to detect changes in clinical endpoints, the available data suggest the unfavorable physiologic effects of epinephrine translate into worse clinical outcomes. Epinephrine was associated with increased risk of refractory cardiogenic shock, and showed nonsignificant trends toward decreased survival.

Levy et al also switched two patients from epinephrine to norepinephrine due to sustained ventricular tachycardia. By contrast, the only possible advantage seen with epinephrine is a shorter duration of additional inotropic support (e.g., dobutamine).

There were significant limitations. Of 163 patients screened, 106 were excluded from the study, which may limit generalizability to the broader CS population. The definition of refractory shock used in this study is not a widely accepted one, and included elevated serum lactate in the diagnostic criteria. Epinephrine use is associated with excess lactic acid production (known as type B lactic acidosis); therefore, lactate may not perfectly reflect tissue perfusion. It is also important to remember that CS develops because of a wide variety of cardiac pathology, with varying hemodynamics. The Levy et al study only included post-AMI CS.

Until larger trials are performed in CS, we have to rely on the available data. Based on the findings of Levy et al, it seems that epinephrine is associated with unfavorable hemodynamic effects and may be associated with worse clinical outcomes in post-AMI CS.