BACKGROUND Myocardial reperfusion with the use of primary percutaneous coronary
intervention (PCI) including stent implantation is the most efficacious treatment for
patients with (STEMI) and improves prognosis significantly. Due to continuous
improvements in the treatment, the mortality for patients with STEMI has decreased
dramatically, but despite these improvements, the mortality rate seems to have reached a
plateau at around 10% within 1 year. In addition, 10% develop clinical heart failure with
a per se 50% mortality rate within 5 years. Moreover, congestive heart failure is
associated with a highly impaired quality of life due to fatigue dyspnea and reduced
exercise capacity. Thus, there is a need for further improvement in the treatment to
drive the event rates further down. One such key target is reducing the damage to the
heart muscle (infarct size) to preserve the heart function and prevent mortality and
heart failure. One major driver of infarct size is reperfusion injury which may account
for up to 50% of the damaged myocardium. Reperfusion injury occurs within the first
minutes to hours after the restoration of the blood flow in the occluded artery and
reperfusion therapy can therefore be considered a "double-edged sword", since the
ischemic injury may additionally be worsened by reperfusion injury. However, the
phenomenon of reperfusion injury is not completely understood, and no preventive
treatments exist. Multiple pathophysiological factors may contribute to reperfusion
injury of which inflammation has been described as a key factor.
Inflammation is induced immediately after the onset of acute myocardial ischemia and is
subsequently exacerbated following reperfusion. Hence, inflammation per se may drive
excessive cardiomyocyte death resulting in decreased contractility and increased infarct
size post-STEMI. Moreover, in the course following STEMI and subsequently reperfusion,
the myocardium starts healing and scarring resulting in remodelling of the ventricle
potentially causing either compensatory hypertrophy or thinning of the myocardium, which
may lead to reduced left ventricle ejection fraction (LVEF) and heart failure. Of note,
inflammation plays a critical role in ventricular remodeling post-AMI, thus inflammation
in relation to reperfusion injury may extend myocardial damage following STEMI.
Glucocorticoids are crucial in the regulation of the systemic inflammatory response and
may therefore be beneficial in limiting myocardial injury following STEMI.
Glucocorticoids mediate two different mechanisms: the genomic effect mediated by
glucocorticoid receptor occupation, gene transcription, and translation within the cell
which is induced within hours, and the non-genomic effect, which is induced rapidly (<15
minutes) after administration via plasma membrane-bound receptors and independent of
cytosolic receptor occupation and genomic regulation. Some of the proposed nongenomic
effects of glucocorticoids on the cardiovascular system included decreased vascular
inflammation and reduced infarct size, cardio protection through membrane stabilisation,
and increasing contractility of the vascular smooth muscle cells. Of note, high
single-dose glucocorticoid (methylprednisolone) (>250 mg), known as pulse therapy has
been proven lifesaving in serval acute conditions including acute rheumatic diseases,
exacerbations in lung diseases, imminent cerebral incarceration, and lately COVID-related
pulmonary incapacity. The beneficial acute effects of pulse glucocorticoid therapy in
these conditions are thought to be mediated by the nongenomic effects of glucocorticoids
via plasma membrane-bound receptors, and the estimated complete glucocorticoid receptor
occupation is reached at approximately 100 mg methylprednisolone, reaching maximum
activation around 250 mg. Moreover, long-term treatment with glucocorticoids is
associated with a series of side effects, whereas short-term treatment only has a few
side effects. Considering this knowledge of the dual effects of glucocorticoids, safety,
and advances in reperfusion strategies, glucocorticoids may now add additional beneficial
role in limiting infarct size and improving prognosis in patients with STEMI. Systemic
intravenous short-term treatment with glucocorticoids could therefore add an important,
beneficial, and safe therapeutic role in limiting the degree of myocardial injury and
thereby improving prognosis in patients with STEMI.
In summary, STEMI remains one of the leading causes of mortality globally despite
significant advances in reperfusion therapies with timely primary PCI, one in five
patients develop heart failure or died within one year following STEMI. The main driver
for mortality and heart failure following STEMI is infarct size which is related to
ischemia- and reperfusion-induced inflammatory response. Thus, inflammation is an
important factor in acute myocardial ischemia and reperfusion injury, which is why
inflammation per se is a feasible and desirable target for improving prognosis in these
patients. To reduce the degree of inflammation effectively and adequately, intervention
is to be made as soon as possible as close to initiation of ischemia, as recognized from
patients' symptom debut, and before revascularization with primary PCI in the prehospital
setting since the effect is more pronounced if the treatment is initiated early after the
onset of STEMI. In addition to reperfusion induced inflammation, ischemia itself,
immediately after occlusion of the artery, induces inflammation. Hence, initiation of the
intervention in the ambulance is needed to harvest the potentially beneficial and
immediate nongenomic effects and subsequent protective genomic actions of pulse
glucocorticoid therapy as soon as possible. Thus, by performing intervention in the
pre-hospital setting, the investigators expect that participation in the trial will have
the potential to produce a direct clinically relevant benefit for the patient resulting
in a measurable health-related improvement alleviating the suffering and potentially
improving the health of the patient and the prognosis of the medical condition.
HYPOTHESIS In patients with STEMI undergoing primary PCI, 250 mg methylprednisolone
administrated in the pre-hospital setting limits reperfusion injury and reduce final
infarct size measured by late gadolinium enhancement (LGE) on cardiac magnetic resonance
(CMR) 3 months after STEMI.
SAMPLE SIZE The primary endpoint is final infarct size (% of left ventricle mass)
measured by LGE on CMR at 3 months. Based on results of the CMR sub-studies of the
DANAMI-3 trial, the mean final infarct size measured by LGE on CMR is 13% with a standard
deviation (SD) of 9% in patients with STEMI. To demonstrate a relative reduction in final
infarct size of 20% with a two-sided alpha level of 0.05 and a power of 80%, recruitment
of 378 patients is needed. A drop-out rate of 40% is expected for the primary endpoint.
Therefore, the investigators expect to randomize 530 patients in total. However, patients
will be included until 378 patients have completed the CMR at 3 months. The power
calculations have been calculated by a biostatistics professor.
