Clinical trial NCT02290080: Determination of the Role of Oxygen in Suspected Acute Myocardial Infarction by Biomarkers
Official title: Determination of the Role of Oxygen on Mechanisms Involved in Ischemia-reperfusion Injury in Suspected Acute Myocardial Infarction by Biomarkers. A Sub Study to the DETO2X-AMI Trial.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Acute Myocardial Infarction (AMI)
Acute Coronary Syndrome (ACS)
ST Elevation (STEMI) Myocardial Infarction
Ischemic Reperfusion Injury
Non-ST Elevation (NSTEMI) Myocardial Infarction
Angina, Unstable
Keywords: acute myocardial infarction (AMI)
acute coronary syndrome (ACS)
ST-segment elevation myocardial infarction (STEMI)
Non ST-segment elevation myocardial infarction (NSTEMI)
Ischemic Reperfusion injury (IR-injury)
Biomarkers
Oxygen
Apoptosis
Fluorescence-activated cell sorting (FACS)
Flow cytometry
Matrix metalloproteinase (MMP)
Lead sponsor: Karolinska Institutet
Sponsor class: OTHER
Collaborators: name: University Hospital, Linkoeping
First posted: 2014-11-13
Enrollment: 175
Sex: ALL
Minimum age (years): 30
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Oxygen treatment is widely used in acutely ill patients, both pre-hospital and in hospital. The indication for oxygen is sometimes unquestionable, such as in many hypoxic patients, but in other situations its use is more of a practise and much less based on scientific evidence. In particular, oxygen treatment is routinely used in patients with a suspected heart attack and variably recommended in guidelines, despite very limited data supporting a beneficial effect. Indeed, a few studies even indicate that oxygen treatment might be harmful.

Immediate re-opening of the acutely blocked artery to the heart muscle is the treatment of choice to limit permanent injury. However, the sudden re-initiation of blood flow achieved with primary percutaneous coronary intervention (PCI), the reopening and stenting of the blocked vessel, can give rise to further endothelial and myocardial damage, so-called reperfusion injury. Ischemia and reperfusion associated myocardial injury (IR-injury) involves a wide range of pathological processes. Vascular leakage, activation of cell death programs, thrombocytes and white blood cells leading to extended inflammation and formation of clots are examples of those effects.

The role of oxygen treatment on these pathological processes, on the extent of IR-injury and the final infarct size in patients with acute myocardial infarctions (AMI) has not previously been studied.

In an ongoing national multicentre, randomized, registry based clinical trial, the DETO2X-AMI trial (NCT01787110), the effect of oxygen on morbidity and mortality in ACS patients is being investigated.

The present DETO2X-biomarkers study is a substudy of the DETO2X-AMI trial, evaluating the effect of oxygen treatment on biological systems involved in the pathogenesis of reversible and irreversible myocardial damage and cell death in ACS.

Detailed description: The DETermination of the role of OXygen i suspected Acute Myocardial Infarction (DETO2X-AMI) trial (NCT01787110), an ongoing multicentre, randomized, registry based clinical trial, is investigating the effect of oxygen on morbidity and mortality in ACS patients.

The present DETO2X-biomarkers study is a substudy of the DETO2X-AMI trial, evaluating the effect of oxygen treatment on biological systems involved in the pathogenesis of reversible and irreversible myocardial damage and cell death in ACS.

AIMS

To evaluate the effect of oxygen treatment on markers of oxidative stress in ACS patients. To assess the effect of oxygen treatment on soluble markers of apoptosis, MMPs and TIMPs in ACS patients.

To study the effect of oxygen treatment on systemic inflammatory activity and leukocyte activation.

To evaluate the effect of oxygen treatment on platelet activation in ACS patients.

HYPOTHESIS

The main hypothesis is that oxygen treatment enhances oxidative stress, systemic inflammation, and markers of apoptosis and MMPs in ACS patients, thereby potentially increasing myocardial damage and cell death, and worsening the prognosis.

STUDY DESIGN and POPULATION

The present study is a biomarker substudy of the DETO2X-AMI trial. The design and population of the DETO2X-AMI trial has previously been described in detail (NCT01787110). All patients included in the DETO2X-AMI trial at Södersjukhuset Stockholm and University Hospital Linköping during the study period specified below are also eligible to be included in the DETO2X-biomarkers study. We intend to include 150 patients with suspected AMI.

STUDY PLAN

All study participants in the DETO2X-biomarkers study have been allocated to receive oxygen (6L/min) or no oxygen treatment as part of the DETO2X-AMI trial. To a variable degree, the participants have already started this treatment when entering the biomarker substudy. Baseline blood samples will be collected as soon as possible after inclusion in the DETO2X-AMI trial, preferably prior to initiation of oxygen treatment. Study subjects will then continue to receive their allocated DETO2X-AMI study treatment. A second set of blood samples will be collected 5-7 hours after randomisation in the DETO2X-AMI trial, and always prior to discontinuation of oxygen treatment.

ANALYSIS of blood samples

As a marker of oxidative stress, plasma-isoprostane will be measured using gas chromatography combined with a massspectrometric detector. Soluble markers of apoptosis, MMP-2 and TIMP-2 will be analyzed by Luminex. Plasma inflammatory markers (C-reactive protein (CRP) and interleukin (IL)-6), myeloperoxidase, and markers of platelet activation will be analysed by ELISA. Flow cytometry will be used to analyse neutrophil integrin receptors and platelet-leukocyte aggregates in whole blood. Whole blood will be fixated and red blood cells lysed before analysis.

EFFICACY OUTCOME

To determine the effect of oxygen treatment on biomarkers of oxidative stress, apoptosis, matrix metalloproteinases, markers of inflammation, and leukocyte and platelet activation in patients admitted to hospital due to suspected AMI.

SUMMARY

The DETO2X-AMI trial will address the effects of oxygen on morbidity and mortality in ACS patients. The present DETO2X-biomarkers substudy is evaluating effects of oxygen treatment on biological systems involved in the pathogenesis of reversible and irreversible myocardial damage and cell death in ACS and may add essential new knowledge to the mechanistics of ischaemic myocardial injury.

Eligibility criteria: Inclusion Criteria:

* symptoms (chest pain, dyspnea) indicating acute myocardial ischemia within the last 6 hours
* ECG changes (ST-segment elevation ≥ 2 mm V1-V4, or ≥ 1 mm in other leads, ST-segment depression \>1 mm in any lead, negative T-wave in leads V2-V6, pathological Q-wave in at least 2 adjacent leads), left bundle branch block

and/or elevated levels of cardiac troponin levels in the emergency department indicating acute myocardial ischemia

* oxygen saturation ≥90% (pulse oximeter)
* age ≥30

Exclusion Criteria:

* unwillingness to participate
* inability to comprehend given information
* continuous oxygen delivery at home prior to inclusion
* cardiac arrest prior to inclusion

Primary outcomes:
measure: Plasma concentration levels over time of biomarkers of oxidative stress, apoptosis, inflammation and platelet aggregation
timeFrame: Within 8hours from baseline
Secondary outcomes:
Other outcomes:
Locations:
city: Linköping
country: Sweden
facility: Linköping University Hospital
city: Stockholm
country: Sweden
facility: Södersjukhuset
Study officials:
affiliation: Department of Medical and Health Sciences, Linköping University, and Department of Cardiology, University Hospital, 58185 Linköping, Sweden
name: Lennart Lennart, MD, PHD
role: PRINCIPAL_INVESTIGATOR
References:
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citation: Hofmann R, James SK, Svensson L, Witt N, Frick M, Lindahl B, Ostlund O, Ekelund U, Erlinge D, Herlitz J, Jernberg T. DETermination of the role of OXygen in suspected Acute Myocardial Infarction trial. Am Heart J. 2014 Mar;167(3):322-8. doi: 10.1016/j.ahj.2013.09.022. Epub 2013 Dec 19.
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