Clinical Outcome and Cost-effectiveness of Reduced Noradrenaline by Using a Lower Blood Pressure Target in Patients with Cardiogenic Shock from Acute Myocardial Infarction: A Multicenter Randomized Trial

Yearly around 6000 patients in the Netherlands suffer from cardiogenic shock
(CS) due to acute myocardial infarction (AMI) and this number is increasing
based on demographic developments. Mortality in CS is still as high as 50%. CS
occurs after large AMI causing loss of function of the heart muscle. The poor
pumping function leads to a state with low blood flow to end-organs with
subsequent multi-organ failure with
high mortality rates. Renal failure and subsequent renal replacement therapy
occur due to low blood flow to the kidneys and is a surrogate marker for
end-organ perfusion and a strong predictor for death in CS.

The first-line pharmacologic strategy in CS is noradrenaline, as recommended by
scientific statements. Noradrenaline is a vasopressor drug routinely used in
the treatment of CS, in the assumption that maintaining a mean arterial blood
pressure (MAP) >= 65 mmHg will improve myocardial and organ (e.g.renal) blood
flow. However, there is no evidence that noradrenaline improves patient
outcomes. Firstly, pharmacologically induced improvement of blood pressure has
not been associated with better survival. Secondly, there is no evidence that
an increase in MAP, if achieved by noradrenaline, leads to greater myocardial
and other end-organ blood flow. As a matter of fact, its vasoconstrictive
properties reduce flow
to the microcirculation of the organs as can be frequently seen by discoloring
of skin in patients treated with noradrenaline. And lastly, noradrenaline is
associated with adverse events such as (supra-)ventricular arrhythmias that
reduce the efficacy of the myocardial pumping function and increase the
myocardial oxygen demand. This can lead to expansion of the myocardial
infarction and worsening of the heart muscle function.

The current, scientifically weak recommendation for noradrenaline (Class IIb)
is based on one study that compared noradrenaline with dopamine in a population
with all types of shock. The overall trial was neutral and only in a small
subgroup a trend was reported towards lower 28-day mortality and less
arrhythmias in CS patients treated with noradrenaline. However, there are
serious methodological concerns as randomization was not stratified and the
test for subgroup differences suggests that the effect was likely based on
chance. In light of the aforementioned limitations the optimal first-line
treatment and MAP target in CS remains unclear.

This study has been transitioned to CTIS with ID 2024-510892-40-00 check the CTIS register for the current data.

The objective of this study is to evaluate the (cost-)effectiveness of reduced
noradrenaline in patients with CS by using a lower MAP target of >= 55 mmHg,
compared to usual care. We hypothesize that reduced use of noradrenaline will
improve overall survival and decrease renal failure requiring renal replacement
therapy. A combined clinical endpoint of mortality and renal replacement
therapy is an accepted endpoint for CS. The need for cost-effectiveness
analysis relies on the fact that we expect that reduced use of noradrenaline is
safe and effective and will therefore reduce costs.

An open label, multicenter randomized controlled trial to ensure level 1
evidence for superiority of the intervention. The usual care arm will provide a
reliable basis for the cost-effectiveness analysis. Patients will be randomly
assigned (1:1) to the intervention or usual care group.

Reduced administration of noradrenaline by using a lower blood pressure target
(mean arterial pressure >= 55 mmHg).

Patients included in this study will not be exposed to additional
investigations that are not part of standard care. They are however requested
to fill out questionnaires at four moments in time.
Patients in the interventional arm will be exposed to a lower blood pressure.
In order to ensure safety, organ functions will be closely monitored. Patients
in the ususal care arm might unnecassary be exposed to noradrenaline and its
accompanying side-effects.