Angina, Unstable Clinical Trial
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.
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.
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.
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