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

Sponsor

Thomas Engstrom (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05462730

Collaborator

(none)

400

Enrollment

Arms

Anticipated Duration (Months)

Study Details

Study Description

Brief Summary

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)

Condition or Disease	Intervention/Treatment	Phase
ST Elevation Myocardial Infarction Inflammatory Response Myocardial Reperfusion Injury Myocardial Injury	Drug: Methylprednisolone Drug: Isotonic saline	Phase 2

Detailed Description

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 25% with a two-sided alpha level of 0.05 and a power of 80%, recruitment of 242 patients is needed. A drop-out rate of 40% is expected for the primary endpoint. Therefore, the investigators expect to randomize 400 patients in total. However, patients will be included until 242 patients have completed the CMR at 3 months. The power calculations have been calculated by a biostatistics professor.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

400 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Investigator-initiated, 1:1 randomized, multicenter, double-blind, placebo-controlled clinical trial. A minimum of 242 patients with STEMI will be randomized 1:1 to an infusion of 250 mg (4 mL) methylprednisolone in the pre-hospital setting prior to primary PCI. The methylprednisolone will be given as a bolus infusion of 1 x 250 mg (1 x 4 mL) over a period of 5 minutes. Patients allocated to placebo will receive 4 mL of isotonic saline (NaCl 0.9%).Investigator-initiated, 1:1 randomized, multicenter, double-blind, placebo-controlled clinical trial. A minimum of 242 patients with STEMI will be randomized 1:1 to an infusion of 250 mg (4 mL) methylprednisolone in the pre-hospital setting prior to primary PCI. The methylprednisolone will be given as a bolus infusion of 1 x 250 mg (1 x 4 mL) over a period of 5 minutes. Patients allocated to placebo will receive 4 mL of isotonic saline (NaCl 0.9%).

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

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

Anticipated Study Start Date :

Oct 1, 2022

Anticipated Primary Completion Date :

Jan 1, 2026

Anticipated Study Completion Date :

Jan 1, 2027

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Methylprednisolone 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.	Drug: Methylprednisolone A dosis of 250 mg methylprednisolone is suspended in isotonic saline to a total volume of 4 mL prior to infusion. Other Names: Solu-Medrol
Placebo Comparator: Isotonic saline A bolus infusion of 4 mL isotonic saline (NaCl 0.9%).	Drug: Isotonic saline A bolus infusion of 4 mL isotonic saline (NaCl 0.9%). Other Names: Isotonic NaCl, Placebo

Arm

Intervention/Treatment

Active Comparator: Methylprednisolone

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.

Drug: Methylprednisolone

A dosis of 250 mg methylprednisolone is suspended in isotonic saline to a total volume of 4 mL prior to infusion.

Other Names:

Solu-Medrol

Placebo Comparator: Isotonic saline

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

Drug: Isotonic saline

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

Other Names:

Isotonic NaCl, Placebo

Outcome Measures

Primary Outcome Measures

Final Infarct size [3 months following STEMI]
% of the left ventricle mass measured by late-gadolinium enhancement (LGE) on cardiac magnetic resonance (CMR)

Secondary Outcome Measures

The extent of MVO [During admission]
Microvascular obstruction (MVO) within the LGE identified on CMR
The extent of haemorrhage [During admission]
The extent of haemorrhage identified on T2*-sequences on CMR
Bolus CFR, IMR, absolute CFR and MRR [During primary PCI]
Bolus CFR, IMR, absolute CFR and MRR measured with a pressure wire following primary PCI
LVEF [During admission and 3 months following STEMI]
LVEF on TEE during admission and 3 months following STEMI
All-cause mortality and hospitalization for heart failure [1 year following STEMI]
All-cause mortality and hospitalization for heart failure at 1 year
Peak Troponin-T and CKMB [During admission]
Peak Troponin-T and CKMB during admission
Makers of inflammation [At admission and 24 hours after admission]
High sentitivity C-reactive protein (hsCRP), leukocyte- and differential count, plasma cytokine levels (IL-1b, IL-2, IL-4, IL-5, IL-7, IL-8, IL-10, IL-12, IL-13, IL-17A, G-CSF, GM-CSF, MCP-1, MIP-1beta, INF-g, tumor-necrosis factor alfa (TNF-alfa), and procalcitonin
Safety: Incidence of adverse events [7 days following admission]
Safety outcome on adverse events
CMR efficacy: MVO [During admission]
Microvascular obstruction as a binary outcome (precence/absence): Hypodense areas within the LGE areas
CMR efficacy: Area at risk [During admission]
Visible edema (hypodense areas) on 3D CINE SAX images
CMR efficacy: Extent of Edema [During admission]
hypodense areas on 3D CINE SAX images
CMR efficacy: MSI [During admission and 3 months following STEMI]
Myocardial salvage index (MSI)=infarct size/area-at-risk. MSI will be measured and calculated at the acute CMR and follow-up CMR
CMR efficacy: LVEF [During admission and 3 months following STEMI]
Evaluated on 3D CINE SAX images at the acute and follow-up CMR.
CMR efficacy: Change in infarct size [During admission and 3 months following STEMI]
Calculated as: Follow-up infarct size/acute infarct size. Measured in %.
CMR efficacy: Changes in LVEF [During admission and 3 months following STEMI]
Changes from baseline LVEF to follow-up LVEF on CMR. Measured in %.

Other Outcome Measures

Pre-PCI and post-PCI TIMI-flow [During primary PCI]
Pre- and post-PCI thrombosis in myocardial infarction (TIMI) flow
CRP, p-glucose, and BNP [During admission]
C-reactive protein (CRP), p-glucose, pro-brain natriuretic peptide (BNP)
Arrythmia [Immediately after discharge]
Ventricular tachycardia/ventricular fibrillation leading to cardioversion from inclusion to hospital discharge
Killip Class [At admission]
Killip Class at admission
All-cause mortality and hospitalization for HF [10 years following STEMI]
All-cause mortality and hospitalization for heart failure

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Age ≥18 years including fertile women (It is not possible to perform a pregnancy test (HCG urine test) in the pre-hospital setting. However, methylprednisolone is not contraindicated in pregnant women).
Acute onset of chest pain with < 12 hours duration.
STEMI as characterized on electrocardiogram (ECG) by 2 mm ST elevation in 2 or more V1 through V4 leads or presumed new left bundle branch block with minimum of 1 mm con-cordant ST elevation or 1 mV ST elevation in the limb lead (II, III and aVF, I, aVL) and V4-V6 or ST depression in 2 or more V1 through V4 leads indicating posterior acute myocardial infarction (AMI).

Exclusion Criteria:

Presentation with cardiac arrest (out of hospital cardiac arrest (OHCA)).
Time from symptoms onset to primary PCI > 12 hours.
Known allergy to glucocorticoid or known mental illness with maniac or psychotic episodes.
Patients with previous acute myocardial infarction (AMI) in the assumed culprit artery.
Previous coronary artery bypass graft (CABG).