The overall primary objective of the PULSE-MI trial is to test the hypothesis that
      administration of single-dose glucocorticoid pulse therapy in the pre-hospital setting
      reduces final infarct size in patients with ST-segment elevation myocardial infarction
      (STEMI) treated with primary percutaneous coronary intervention (PCI)

Pulse Glucocorticoid Therapy in Patients With ST-Segment Elevation Myocardial Infarction

ST Elevation Myocardial Infarction

Inflammatory Response

Myocardial Reperfusion Injury

Myocardial Injury

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.

Methylprednisolone

Isotonic saline

% of the left ventricle mass measured by late-gadolinium enhancement (LGE) on cardiac magnetic resonance (CMR)

Professor, MD, Ph.D., DMSc

Microvascular obstruction (MVO) within the LGE identified on CMR

The extent of haemorrhage identified on T2*-sequences on CMR

Microvascular obstruction as a binary outcome (precence/absence): Hypodense areas within the LGE areas

Visible edema (hypodense areas) on 3D CINE SAX images

Myocardial salvage index (MSI)=infarct size/area-at-risk. MSI will be measured and calculated at the acute CMR and follow-up CMR

Evaluated on 3D CINE SAX images at the acute and follow-up CMR.

Calculated as: Follow-up infarct size/acute infarct size. Measured in %.

Changes from baseline LVEF to follow-up LVEF on CMR. Measured in %.

Peak Troponin-T and CKMB during admission

All-cause mortality and hospitalization for heart failure at 3 months

A five minutes bolus infusion of 250 mg (4 mL) methylprednisolone to inhibit inflammatory damage following ST-segment elevation myocardial infarction. The infusion of methylprednisolone will be given in the pre-hospital setting prior to primary PCI.

A bolus infusion of 4 mL isotonic saline (NaCl 0.9%).

Pulse Glucocorticoid Therapy in Patients With ST-Segment Elevation Myocardial Infarction

About this trial

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Placebo

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