Clinical Trial Details
— Status: Active, not recruiting
Administrative data
| NCT number |
NCT02886273 |
| Other study ID # |
StavangerSCA |
| Secondary ID |
|
| Status |
Active, not recruiting |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
January 2007 |
| Est. completion date |
August 1, 2022 |
Study information
| Verified date |
January 2021 |
| Source |
Helse Stavanger HF |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational [Patient Registry]
|
Clinical Trial Summary
Sudden cardiac death (SCD) is a major cause of mortality in industrialized countries and
represents a major health issue. The survival rate after out-of-hospital cardiac arrest
(OHCA) is only 10-15%, regardless of first recorded rhythm. Prior heart disease is a major
risk factor for sudden cardiac arrest (SCA), and coronary artery disease (CAD) is the most
common underlying cause. A better understanding of pathophysiological mechanisms occurring
during cardiac arrest (CA), earlier diagnosis of underlying cause as well as identification
of risk factors related to CA may improve patient treatment and increase survival. In our
out-of-hospital cardiac arrest (OHCA)-study, we intend to investigate whether biomarkers,
such as copeptin, hs-cTnT and NT-proBNP in addition to clinical evaluation may improve risk
stratification and supply information related to pathophysiology.
Furthermore, we intend to gather additional pathophysiological information related to
coagulation activation in CA and cardiopulmonary resuscitation (CPR), as intravascular
thrombosis may impair microcirculation and reduce end-organ blood flow which is associated
with a poor prognosis. We intend to study coagulation activation during and immediately after
SCA with regard to outcome, and assess the contribution of the intrinsic system, measured
together with that of the extrinsic system.
Low levels of n-3 fatty acids (FA) are reported as a risk factor for SCD. Red blood cell
eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA) may serve as a useful surrogate of
cardiac omega-3 fatty acid status. The exact mechanism by which FAs might protect against
serious cardiac arrhythmias is not known, but they are expected to exert a membrane
stabilizing effect during an ischemic episode. In our study we intend to evaluate the
association between ventricular fibrillation (VF) and the content of EPA and DHA in red blood
cells. Furthermore, as vitamin D is associated with n-3 FAs in the diet, we also aim at
investigating the association between 25-hydroxy (OH)-vitamin D and VF.
Description:
Background:
Sudden cardiac death (SCD), also termed sudden cardiac arrest (SCA), accounts for
approximately 15 percent of the total mortality in industrialized countries. In Europe, the
incidence of out-of-hospital Emergency Medical Services (EMS) attended sudden cardiac arrest
(SCA) is estimated to 81.6/100 000 person-years, 52.5 % of which is presumed to have a
cardiac cause [1]. Coronary artery disease (CAD) is the most common underlying heart disease
associated with out-of-hospital cardiac arrest (OHCA) [2]. SCD is the initial presentation of
CAD in 15 percent of CAD-patients [3]. Furthermore, it is also the most frequent mechanism of
death in patients with known CAD, accounting for 40-50 percent of CAD-mortality [4]. Compared
to healthy subjects the incidence of SCD is six- to tenfold higher in the presence of
clinically recognized heart disease [5], and cardiomyopathies represents the second largest
cause of SCD [6]. Despite early advanced cardiopulmonary resuscitation (CPR) provided by the
EMS the mortality rate remains high [1]. Due to the dramatic consequence of SCA,
understanding of pathophysiological mechanisms and early identification of etiology is
essential to improve outcome.
SCA due to VF may be the presenting symptom of acute myocardial ischemia or may be a
consequence of scarring due to a previous myocardial infarction (MI). Cardiac troponin (c-Tn)
is the most commonly used biomarker for diagnosing an acute myocardial infarction (AMI) [7].
Although earlier detection of AMI may be obtained by the introduction of high sensitivity
(hs)-cTn assays, there still remains a troponin-blind period very early after symptom onset
[8, 9], with the need for serial blood sampling to diagnose or exclude an AMI [7, 9].
Furthermore, there are challenges related to the specificity of elevated levels of hs-cTn
[10, 11]. Therefore, measurement of hs-cTn in a single blood draw in the ambulance or at
admission may not provide sufficient information for the diagnosis of AMI among patients with
OHCA.
Lately, several studies have demonstrated an incremental diagnostic value of copeptin when
added to conventional cTn or hs-cTn for early detection of AMI [12, 13]. Copeptin levels peak
early (0-1 h) after symptom onset and are already increased at the time of first medical
contact in the ambulance for patients with MI [8]. Copeptin used in combination with hs-cTn
may therefore improve the diagnosis of AMI in very early presenters, and help differentiating
the underlying cause of SCD.
Copeptin has also been demonstrated to be an independent predictor of adverse events
following MI [14] and is shown to be associated with outcome after OHCA [15, 16]. Less is
known about the prognostic value of troponins in patients experiencing a cardiac arrest (CA).
Higher values of hs-cTnT are seen in one-year non-survivors as compared to survivors of OHCA,
although not shown to be an independent predictor of 12-months survival [10]. In our study,
the objective will be to evaluate the diagnostic and prognostic utility of hs-cTnT and
copeptin in SCA patients.
Patients with heart failure are at increased risk for ventricular arrhythmias and SCD. B-type
natriuretic peptide (BNP) and N-terminal proBNP (NT-proBNP) have been demonstrated to be
useful diagnostic tools to rule out both chronic and acute heart failure [17]. Little is
known about the natural course of natriuretic peptides during a SCA event, but BNP is
demonstrated to be an independent predictor of long-term mortality [18], as well as survival
to hospital discharge after OHCA of cardiac origin [19]. There is also a well-documented
association between BNP or NT-proBNP and the short- and long-term risk of death in patients
with acute coronary syndrome (ACS) [20, 21]. In our study, we intend to investigate the
diagnostic and prognostic utility of NT-proBNP sampled during or immediately after OHCA.
The overall survival rate after OHCA is low. Even in successfully resuscitated patients
admitted to the intensive care unit (ICU), the prognosis remains poor. Former studies have
shown a marked activation of blood coagulation, with a concomitant inadequate activation of
the endogenous fibrinolytic system, in resuscitated OHCA-patients [22-25]. Intravascular
clotting and "no reflow" in the microvasculature represent a barrier to successful end-organ
perfusion and may influence the outcome in cardiac arrest (CA) patients [26]. Understanding
the pathophysiological mechanisms of CA is important to guide management and improve outcome.
Plasma thrombin-antithrombin (TAT) complexes, fibrin monomers (FM) and D-dimer are used as
specific markers of activated blood coagulation. Previous studies have shown markedly
increased TAT-levels in patients with nontraumatic OHCA [22, 23]. Admission TAT is also shown
to be a useful prognostic marker in resuscitated OHCA patients and is independently
associated with survival after resuscitation from CA [24]. D-dimer levels are found to
increase after CA and CPR [22, 27]. Accordingly, Adrie et al. [28] demonstrated high
admission levels of D-dimer in all OHCA patients. Furthermore Szymanski et al. [29] reported
higher D-dimer concentrations on admission to be a strong and independent predictor of
mortality in OHCA patients. In our study, we intend to study the activation of blood
coagulation, including both the extrinsic- and the intrinsic coagulation pathways, during and
immediately after SCA with regard to outcome.
Most interventions to date do not directly affect the transient pathophysiologic event
initializing potentially fatal arrhythmias. Instead, they attempt to alter and prevent
underlying disease like CAD. Animal studies have shown that fish oils are protective against
ischemia-induced VF [30]. Support for these data comes from the Physicians' Health Study
[31], which is a prospective study of 20 551 men aged 40 to 84, free of cardiovascular
disease at baseline, with a follow-up period of 11 years. As compared to consumption of fish
less than once a month, fish intake at least once per week was associated with a reduced risk
of SCD (RR 0.48). In the same study there was no reduction in the risk of total myocardial
infarction, non-sudden cardiac death or total cardiovascular mortality, and the protective
effect of fish was suggested to be due to a reduction in fatal ventricular arrhythmias. It
has been hypothesized that the lower risk of SCD with higher fish intake may be related to
the long-chain n-3 polyunsaturated fatty acids (PUFAs) EPA and DHA found in fish. Consistent
with this hypothesis are the observations from the physicians' Health Study [31] that the
risk of SCD was significantly lower in subjects with blood n-3 FA levels in the highest as
compared to the lowest quartile. The same potential effect of fish oils to protect against
SCD was illustrated in the randomized, open-controlled GISSI-prevention study [32]. Patients
with a recent myocardial infarction receiving n-3 FAs supplements had a significant lower
incidence in the combined endpoint of death plus nonfatal infarction and nonfatal stroke at
42 months (12.6 versus 13.9%). After adjustment for risk factors, all of the observed benefit
was due to a 20 % reduction in the risk of death, mostly due to reduction in SCD. However, a
study of 200 patients secured with an ICD (implantable cardioverter defibrillator) following
an episode of ventricular tachycardia (VT) or VF, has not shown a reduction in the recurrence
of these arrhythmias after supplementation with EPA/DHA. In that study there was actually a
trend toward a higher incidence of VT/VF in patients randomized to EPA/ DHA substitution
[33]. In that setting the underlying mechanism for the generation of VF might, however, not
be ischemic.
The exact mechanism by which FAs might protect against serious cardiac arrhythmias is not
known. They are important constituents of cell membranes and may affect several
electrophysiologic properties, such as resting potential, action potential, repolarization
and refractory period. Alterations in cellular calcium concentration can contribute
significantly to changes in both impulse generation and impulse conduction in myocardial
cells. Incorporation of n-3 fatty acids in the cellular membrane is shown to affect membrane
fluidity which in turn may have an influence on calcium entry or removal. An alternative
mechanism may be changes effected by n-3 FAs on myocardial production of eicosanoids. In
particular the inhibition of thromboxane A2 (TXA2) production is likely to be of significant
pathophysiological benefit, since TXA2 is shown to be implicated in myocardial ischemia and
arrhythmogenesis [34].
A recent study by William S. Harris et al. [35] has shown that levels of EPA/ DHA in cell
membranes of red blood cells (RBC EPA/ DHA) highly correlate with the cardiac EPA/ DHA level.
The RBC response to supplementation was also very similar to that observed in the heart.
Therefore RBC EPA+ DHA may serve as a useful surrogate of cardiac omega-3 fatty acid status.
The investigators expect n-3 FAs to exert a membrane stabilizing effect during an ischemic
episode, and hypothesize that patients suffering VF during the initial phase of their first
AMI presentation have lower levels of RBC EPA/ DHA than matched controls.
Over the last years vitamin D is another dietary supplement found to be associated with
cardiovascular disease. This fat-soluble vitamin, primarily derived from sun-exposure and
fatty fish, has been demonstrated to influence cardiac contractility and myocardial calcium
homeostasis [36], and insufficiency of this vitamin may have deleterious effects on cardiac
autonomic functions as evaluated by heart rate turbulence and heart rate variability [37]. In
prospective studies, severe vitamin D deficiency has been strongly associated with total
mortality, cardiovascular events and SCD [38-42]. In one study of 3299 patients who were
routinely referred to coronary angiography, the authors demonstrated hazard ratios for death
due to heart failure and for SCD of 2.84 (1.20-6.74) and 5.05 (2.13-11.97), respectively,
when comparing patients with severe vitamin D deficiency [25(OH)D <25 nmol/liter)] with
persons in the optimal range [25(OH)D ≥ 75 nmol/liter] [43]. Demonstrated effects on
electrophysiology,contractility, and cardiac structure suggest that vitamin D deficiency
might actually be a causal factor for development of cardiac diseases. The pronounced effect
on SCD found in several studies might be an indication of a possible protective effect of
high vitamin D-levels against ventricular arrhythmias. This is, however, not well studied and
the optimal cut-off-value for protection is not well defined. Therefore, a comparison of the
25-OH-vitamin D levels between different OHCA categories of patients, with and without an
acute coronary event, may be appropriate.
Statistical methods
Statistical analysis will be performed using the statistical package SPSS (Statistical
Package for the Social Sciences). A statistically significant level of p < 0.05 will be
applied for all tests.
EPA/ DHA and vitamin D in the different clinical patient categories will be compared to
controls collected from the RACS (Risk markers in the Acute Coronary Syndromes) database
(NCT00521976).
Ethics and confidentiality
The present study is conducted in accordance with the Helsinki Declaration of 1975 and later
revisions and accepted by the Regional Board of Research Ethics as well as the Norwegian
Health Authorities. Analytic data will be related to patient number and not to patient
identity. According to Norwegian regulations, the family of non-survivors will be informed by
the attending physician and the inclusion of patients needs to be documented in the hospital
records. The family of the deceased is entitled to object to the use of any biological
samples for research purposes. Patients regaining consciousness and mental capability during
their hospital stay will be asked personally for a written informed consent. For the
remaining survivors the next of kin will be asked for permission on behalf of the patient. If
either the patient or the family refuses participation, blood samples already collected at
resuscitation and admission will be destroyed.
