Norepinephrine Bests Epinephrine in Battle of the Vasopressors in Cardiogenic Shock

Norepinephrine appears to be a safer choice than epinephrine for patients with cardiogenic shock complicating acute MI, according to results from a randomized trial. Patients given epinephrine were more likely to develop refractory cardiogenic shock, which led to early termination of the study.

“Compared with norepinephrine, epinephrine administration was also associated with an increase in heart rate, prolonged acidosis, and lactatemia,” write researchers led by Bruno Levy, MD, PhD (Centre Hospitalier Universitaire de Nancy, France).

Although the two agents are among the most commonly used, protocols for patients with cardiogenic shock differ between countries and across hospitals within the same country, noted Bimmer E. Claessen, MD, PhD (Academic Medical Center, Amsterdam, the Netherlands and Icahn School of Medicine at Mount Sinai, New York, NY), who commented on the study for TCTMD.

“I’ve worked in three hospitals in the Netherlands, and all three had different vasopressors or inotropes that they prefer to give in patients with cardiogenic shock,” he said. “So, there are a lot of differences, and everyone has a rationale for why that strategy is preferential, but it's never been investigated well.”

Claessen added that, on a mechanistic level, the findings of the new paper make sense because epinephrine may put extra strain on a heart that is already in trouble. The study was published July 2, 2018, in the Journal of the American College of Cardiology.

Refractory Cases Emerge Unexpectedly

Fifty-seven cardiogenic shock patients from nine hospitals in France were randomized to epinephrine (n = 27) or norepinephrine (n = 30). There were no differences in the percentage of patients in each group who had intra-aortic balloon pump inserted after PCI.

For the primary efficacy endpoint of cardiac index evolution, or change in cardiac index, there were no significant differences between the epinephrine and norepinephrine groups. Similarly, there were no differences in most of the secondary hemodynamic endpoints (ie, mean arterial pressure, systemic vascular resistance index, cardiac power index, pulmonary arterial systolic pressure, wedge pressure, LVEF, biomarkers, or incidence of arrhythmias). At 60 days, mortality was 52% in the epinephrine group and 37% in the norepinephrine group (P = 0.25).

However, compared with the norepinephrine group, those treated with epinephrine had higher heart rates and lactate levels, but a shorter duration of additional inotropic support. Importantly, they also had a greater likelihood of refractory cardiogenic shock (37% vs 7%; P = 0.008), which was not a prespecified endpoint because it was not anticipated to be a problem with either drug. In fact, it was not until excess cases of refractory cardiogenic shock emerged that the investigators defined it as a safety metric—4 years into the start of the study.

In an editorial, Sean van Diepen, MSc, MD (University of Alberta, Edmonton, Canada), notes that this is problematic because “the timing of the endpoint assessment is not provided, and there is no clear pathophysiological mechanism to explain why epinephrine is associated with refractory cardiogenic shock.” He therefore suggests that it “is possible that the composite safety endpoint may be driven solely by differences in type B lactic acidosis.”

Additionally, van Diepen notes that since patients treated with extracorporeal life support (ECLS) often require concurrent inopressor therapies, “there is a potential that the safety outcome could also be confounded by the aforementioned ECLS initiation bias, but a definitive conclusion cannot be reached because the association between the provision of ECLS and refractory cardiogenic shock was not described.”

Refractory cardiogenic shock was defined as sustained hypotension, end-organ hypoperfusion, and hyperlactatemia despite high inotrope and vasopressor doses.

One Size Does Not Fit All

To TCTMD, Claessen said despite some flaws with the study’ design and that it was stopped early, it highlights some of the difficulties of mounting randomized trials in patients with cardiogenic shock.

“It took them 5 years to randomize 57 patients from nine centers,” he observed, adding that it is unlikely that such a trial would be done again with these two agents. Furthermore, Claessen said the study simply builds on existing evidence from the SOAP II trial that norepinephrine likely is the better agent of the two, but these are not the only options available. While the reasons for norepinephrine’s safety advantage over epinephrine are uncertain, he speculated that it probably has to do with differences in their affinity for various types of adrenergic receptors.

In his editorial, van Diepen adds that the current study “advances our understanding of the temporal hemodynamic and biochemical changes attributable to epinephrine when used as a first-line agent” and “informs clinicians that both drugs, when titrated strictly to goal mean arterial pressure, result in similar hemodynamic responses albeit with a few exceptions that may reflect their different pharmacodynamic properties.”

It also suggests, van Diepen notes, that while epinephrine is deleterious in ischemia, pretreatment tachycardia, or those at a high risk of arrhythmias, it theoretically may be advantageous in patients with bradycardia.

But Claessen said while epinephrine is an aggressive therapy that does beneficially increase heart rate in bradycardia patients, there are alternatives such as dobutamine that are likely to be safer. Additionally, he said interest has been steadily increasing in using more hemodynamic support in these patients and implementing ECLS early, especially with the advent of smaller, easier to use devices.

According to van Diepen, there may well be different cardiogenic shock phenotypes that require individualized approaches, something he admits lacks evidence and may be “a false generalization.” Nevertheless, he asserts that there is a need for better taxonomy of these suspected phenotypes and for more research into the underlying etiologies of cardiogenic shock, which could be a step forward in making therapeutic approaches more precise.

Claessen said he has a similar view, noting, "There is no one-size-fits-all, and you should always tailor these approaches to the specific patient. Every patient has a different reason why they go into cardiogenic shock, and therefore you may have reasons why you prefer one medication [over another].”