Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT00465868 |
| Other study ID # |
StaHF461301 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
N/A
|
| First received |
April 24, 2007 |
| Last updated |
July 27, 2015 |
| Start date |
December 2004 |
| Est. completion date |
May 2007 |
Study information
| Verified date |
June 2008 |
| Source |
Helse Stavanger HF |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
Norway:National Committee for Medical and Health Research EthicsNorway: Directorate of Health |
| Study type |
Observational
|
Clinical Trial Summary
KoMPiS is a contrast aided cardiac magnetic resonance study of microvascular obstruction and
left ventricular remodelling following acute revascularised anterior myocardial infarction.
The study will monitor the included patients for 12 months following the acute myocardial
infarct and collect data from MR scans and blood samples. The study is designed to
demonstrate that obstruction of blood flow in the peripheral (small) vessels of the cardiac
muscle is an important factor in the post-MI development of left ventricle dysfunction that
occurs in many patients, despite of a successful re-opening of the occluded coronary artery
that caused the MI.
Description:
Introduction. Cardiovascular disease is responsible for 30 % of worldwide mortality,
accounting for approximately 15 million deaths per year. Improvement in medical treatment
strategies during the last decades has produced a tremendous decrease in mortality in
connection with acute myocardial infarction (AMI). Since the 1960's, short-term mortality
(30 days) has decreased from approximately 30 % to the current mortality rate of 6,5%. The
success of modern treatment of AMI has, however, led to an increasing number of patients
surviving AMI, thus creating a growing group of high-risk patients that need further
treatment and care. The development of heart failure and the risk of recurrent ischemia and
reinfarction are the two main threats to this population. To further improve the treatment
and outcomes in this high risk population, early risk stratification based on a thorough
understanding of the operating mechanisms behind the transition from acute infarction to
heart failure is necessary.
AMI, reperfusion and microvascular obstruction. Reperfusion therapy has been one of the
major successes in the treatment of AMI, and there are numerous studies to support the idea
of opening occluded coronary arteries, especially in the context of an AMI. However, even in
the presence of a patent infarct related artery, there may still be inadequate reperfusion
at the tissue level. This phenomenon, known as no-reflow, may preclude optimal reperfusion
because of microvascular obstruction. It is estimated that microvascular obstruction occurs
in 30-40% of all revascularised patients in spite of a patent artery; the exact underlying
pathophysiological mechanisms are partially unknown. Microvascular obstruction may possibly
be due to sequestration of neutrophils in the microvasculature that subsequently lead to
microvascular occlusion by erythrocytes, leucocytes and cellular debris. It remains unclear
whether the stimulus for the development of microvascular obstruction originates during
coronary occlusion exclusively or if reperfusion plays an active role in progression of the
phenomenon.
Microvascular obstruction and heart failure. The presence of microvascular obstruction
following AMI, predicts unfavourable postinfarction prognosis and development of left
ventricular dysfunction and left ventricular remodelling. Left ventricular remodelling is
associated with development of heart failure and is directly related to the magnitude of
microvascular obstruction early after experimental and clinical AMI1, as well as 6 months
after the acute event. The mechanisms by which microvascular obstruction induces ventricular
remodelling remain unknown. Possibilities include the potentiation of wall thinning and
infarct expansion early after infarction, as well as potential impairment of infarct
healing, given the association between presence of microvascular obstruction and greater
transmural scar formation 6 months after AMI.
Assessment of microvascular obstruction. Until recently, microvascular obstruction could
only be assessed by methods such as radioactive micro-spheres and other histopathological
techniques, that only could be performed at the terminal phase of an experimental study, and
not clinically. However, recent advances in the field of non-invasive cardiac imaging have
enabled the serial assessment of this phenomenon by cardiac magnetic resonance imaging
(CMR), thereby facilitating a much greater understanding of its pathophysiological and
prognostic significance.
Assessment of left ventricular remodelling by CMR. The pathologic changes associated with
the development of heart failure include changes in geometry and function, myocytes and
extracellular matrix. Assessment of left ventricular remodelling includes estimation of left
ventricular size and shape, left ventricular mass and a functional assessment including an
estimation of ejection fraction.
Biochemical markers of scar formation, inflammation and LV dysfunction. Prognosis after MI
is related both to the extent of myocardial cell-loss and the quality and quantity of repair
of the infarcted myocardium. The fate of fibrous tissue following acute myocardial
infarction, including regression, persistence or progression of fibrosis is important for
the understanding of the underlying mechanisms behind the progressive nature of LV
remodelling following AMI. Non-invasive assessment of fibrous tissue formation may be
accomplished by measuring serum markers of collagen turnover.
Following AMI, fibrillar collagen appear both in the infarct scar and remote to the site of
the myocardial infarction, including viable tissue of the infarcted and noninfarcted
ventricles. In rats, procollagen mRNA for collagens type I and III is increased in the right
ventricle from day 2 onwards after a transmural left ventricular MI. The increased collagen
turnover may last for several months or even years.
Aminoterminal propeptide of type I procollagen (PINP) and aminoterminal propeptide of type
III procollagen (PIIINP) are liberated during collagen biosynthesis, and they may be used as
markers of this process. PIIINP reflects the turnover of soft tissue collagen and is
elevated after AMI, reaching a plateau after four days with the largest increase in patients
with large infarctions and acutely reduced LV function. Increased serum PIIINP measured in
the subacute phase of myocardial infarction is associated with persistently depressed LV
ejection fraction, dilatation and restrictive diastolic filling. Patency of the infarct
related artery reduces the PIIINP response and scar formation.
The role of type I collagen following AMI is less clear. It has been suggested that there is
a late rise in the synthesis of type I collagen after myocardial infarction, but this
remains to be shown. Among patients with heart failure of mixed aetiology (ischemic and
non-ischemic), increased levels of CIPT, PINP and PIIINP are associated with an increased
risk of death.
The modulation of collagen deposition and scar formation is accomplished by an intricate
interplay between neurohormones (eg. aldosterone, angiotensin I and II, bradykinins,
catecholamines and natriuretic peptides) and the inflammatory system. The relationship
between CMR, collagen markers and neurohormones is not known in this setting.
Study aims. To characterize disease progression and to elucidate the operative
pathophysiological mechanisms in patients with evidence of microvascular obstruction on
contrast enhanced CMR following acute AMI.
Study plan. This is a single centre observational study, designed to assess differences
between patients with and without CMR evidence of microvascular obstruction. To assure a
homogenous group of patients, only successfully revascularised patients with AMI caused by a
single proximal/mid LAD, CX or RCA occlusion as assessed by coronary angiography, will be
included. Only patients with functionally single vessel disease and without former heart
disease will be included. Patients will be selected for screening and requested to
participate following the acute PCI. The first CMR will be performed at 48±12 hours
following the primary PCI. A follow-up CMR will be performed one week, two months and one
year following the index PCI. At every CMR examination (including the screening phase),
blood samples will be collected, and clinical examination and an echocardiography will be
performed. The study population will be managed during and after their AMI according to
current optimal guidelines, and all patients will be considered for the same medical
therapy, including ACE inhibitors and beta-blockers. The study will evaluate the presence of
microvascular obstruction at baseline vs. changes over time in CMR data and biochemical
markers of collagen turnover, neurohormonal activity and inflammation.
Sample size estimation. To detect a difference in LV mass of 10g with a power of 80% and a p
= 0,05, it is necessary to include 14 patients. To show a difference in ejection fraction of
5% with a power of 90% and p = 0,05, it is sufficient to include 5 patients. In a study by
Wu and coworkers, late enhancement CMR demonstrated a significant difference in clinical
outcome following myocardial infarction when 38 patients (with or without congestive heart
failure) were divided into three groups according to the size of infarction. To account for
dropout and biological variation we will include a minimum of 20 patients with microvascular
obstruction. It is estimated that microvascular obstruction persists in around 30-40% of all
patients undergoing revascularisation. The group of patients without microvascular
obstruction will consequently be 40 patients, generating a total study population of 60
patients.
