Clinical Trial Details
— Status: Enrolling by invitation
Administrative data
| NCT number |
NCT01307735 |
| Other study ID # |
232447 |
| Secondary ID |
|
| Status |
Enrolling by invitation |
| Phase |
N/A
|
| First received |
March 2, 2011 |
| Last updated |
March 2, 2011 |
| Start date |
January 2010 |
| Est. completion date |
July 2011 |
Study information
| Verified date |
February 2011 |
| Source |
Libin Cardiovascular Institute of Alberta |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
Conjoint Health Research Ethics Board of the University of Calgary: |
| Study type |
Observational
|
Clinical Trial Summary
Myocarditis is an inflammatory heart disease primarily of viral origin that can lead to
heart failure and death. Despite an unfavorable long-term outcome and mortality rate as high
as 50%, classification, diagnosis, and treatment of myocarditis remains controversial. The
gold standard for clinical diagnosis is direct sampling of the heart muscle, which often
misses the infected area and thus reliability of the test is questionable. While the cause
and clinical presentation of myocarditis are often unclear, inflammation of the heart muscle
can be clearly imaged by Cardiovascular Magnetic Resonance Imaging (CMR).
Due to recent international consensus on CMR protocol for myocarditis and the unique ability
of CMR to visualize cardiac structure, function, and characterize tissue, CMR has become the
primary tool for clinical assessment. This study aims to test the accuracy of CMR in the
diagnosis of myocarditis and to validate whether CMR acquired in an early stage of
myocarditis can provide incremental prognostic information. In order to effectively gather
relevant clinical data, an online, multi-centre international registry will be established
across twenty different medical institutions.
Hypotheses:
1. CMR accurately detects active myocardial inflammation in patients with myocarditis
2. CMR acquired in an early clinical stage of myocarditis provides incremental prognostic
information superior to standard clinical diagnostic tools.
Description:
Study Rationale Because of its unique combination of morphological and functional imaging
with tissue characterization, cardiovascular magnetic resonance (CMR) has become the
non-invasive diagnostic tool of choice for assessing myocarditis. Recently, standard
diagnostic CMR criteria for myocarditis have been proposed ("Lake Louise Criteria"), based
on signal intensity patterns in T2-weighted images and T1-weighted images before and after
contrast administration 3.
There is however a lack of prognostic data using these criteria. Furthermore, the clinical
utility of these criteria in a real-life scenario is not well understood.
The aim of the study is to evaluate the diagnostic CMR criteria for the prediction of
functional outcome and quality of life in patients with myocarditis.
Background: Myocarditis Myocardial inflammation, most often caused by myocardial involvement
in systemic viral illness, although typically of benign outcome, may result in persisting
myocardial damage. Clinical outcomes include heart failure and death. Chronic myocarditis
can progress to dilated cardiomyopathy which result in dilation and decompensation of one or
both ventricles resulting in heart failure, with the need for cardiac transplantation.
Diagnostic approach to myocarditis The diagnosis of myocarditis is generally considered
after exclusion of other causes of acute heart disease and established by a combination of
history, physical examination with non-invasive or invasive tests.
History and clinical examination have to precede further diagnostic testing although the
initial onset of myocarditis often is insidious, symptoms are non-specific, and clinical
signs absent.
ECG findings, such as ST changes, AV block or arrhythmias may be associated with
myocarditis, although their sensitivity is limited.
Serological biomarkers of myocardial injury such as creatine kinase and troponin may be
increased; however, the prevalence of an increased troponin T in biopsy-proven myocarditis
is limited, likely due to the lack of extensive necrosis in many cases.
Endomyocardial biopsy (EMB) usually is considered the gold standard in definitively
diagnosing myocarditis. In 1986, a group of pathologists defined EMB criteria for the
diagnosis of myocarditis, known as "The Dallas Classification System". This classification
suggested that a minimum of three, but recommended that five separate biopsy specimens had
to be taken for accurate pathological analysis. A major limitation of this technique is that
it is invasive, with a mortality rate of 0.4% and certain contraindications9. Myocardial
injury caused by viral infection could also have a focal distribution, which EMB may not be
able to detect. Only 10 to 25% of patients with clinically suspected myocarditis have
confirmed diagnosis by EMB11. High interobserver variability in the interpretation of EMB,
and with the associated sampling errors, the clinical value of this technique is questioned.
Indium-111(111In)-antimyosin antibody (AMA) scintigraphy uses specific antibodies targeted
at damaged myocytes, and thus, is able to detect in vivo necrosis. A major drawback of this
technique, however, is that it cannot differentiate between different etiologies of
myocardial necrosis. It is also not suitable to detect inflammation in the absence of cell
death.
Prognostic value of diagnostic markers There is a paucity of data on the prognostic value of
the various diagnostic tools. LV dysfunction is considered the most important indicator for
worse outcome in myocarditis. In recent studies, however, LV dysfunction was infrequently
observed3; therefore, this marker may not be helpful in most clinical scenarios, especially
in less severe cases with persisting symptoms despite preserved cardiac function.
Background: Cardiovascular Magnetic Resonance (CMR) Hallmark features of acute myocarditis
are interstitial lymphocytic infiltration with edema and hyperemia, and myocardial
necrosis3. Interestingly, these can be readily identified by CMR in a non-invasive approach,
using a combination of non-contrast and Gadolinium-enhanced techniques.
CMR offers several advantages, as opposed to other diagnostic modalities. It does not use
radiation or harmful contrast agents, the field of view is not limited and tissue
characterization can be combined with functional assessment of the ventricles in the same
session.
The first clinical study using contrast-enhanced magnetic resonance imaging in patients with
acute myocarditis showed that CMR is a suitable tool to detect myocardial inflammation and
showed a spread of tissue changes from focal to diffuse myocardial involvement.
Based on previous pilot data, the same group further introduced T2-weighted CMR imaging in
acute myocarditis as a specific marker for myocardial edema.
Areas of Gd accumulation in CMR images acquired late after contrast administration ("Late
enhancement") reflect irreversible injury and were reported in about 60% of reported
myocarditis cases.
The diagnostic sensitivity of a comprehensive CMR protocol is 67%, with a specificity of 91%
and a diagnostic accuracy of 78%, which exceeds that of other diagnostic approaches. As
sub-clinical myocarditis is also an immune response phenomenon, it is speculated that CMR
parameters used for diagnosing acute myocarditis will also be relevant for imaging
sub-clinical myocarditis. CMR is increasingly accepted as the emerging standard diagnostic
test for myocarditis.
Prognostic CMR data in myocarditis Follow-up data on CMR in myocarditis are still scarce. In
a pilot study, Wagner et al. studied the evolution of the relative enhancement in the early
course of the disease and after months in patients with myocarditis compared with 26 healthy
patients. They demonstrated that myocardial contrast enhancement decreases to normal values
in many patients within a follow-up of 30 months. In 2/19 patients, left ventricular
function did not recover. Interestingly, contrast enhancement on day 28 was predictive of
the ejection fraction and of clinical outcome after 30 months.
More recently, Zagrosek et al. provided CMR follow-up data on 36 patients 18±10 months after
myocarditis. They demonstrated that in the acute phase, T2 ratio and relative enhancement
was elevated in most of the patients (86% and 80% respectively) and significantly decreased
at follow-up, this was associated with improvement both in clinical and left ventricular
function parameters. Late enhancement was present in 22 patients (63%) and persisted in
21/22 patients. The acute phase T2 ratio correlated significantly with the change in
end-diastolic volume.
The predictive value of each of the CMR markers for inflammation (hyperemia, edema) and
necrosis/fibrosis, however, is not known, especially when compared to LV function at
presentation.
Study Objectives
1. The primary objective will be to compare CMR criteria for myocarditis at presentation
with LV volumetric and functional outcome markers as acquired in a follow-up CMR study
in patients with diagnostic CMR criteria for myocarditis and in a control group.
2. Secondary objective will be to compare compare CMR criteria for myocarditis at
presentation with quality of life at 12 months after presentation in the same groups.
Study Variables
1. CMR Criteria for Myocarditis ("Lake Louise Criteria")
Evidence for myocardial inflammation will be present if at least 2 of 3 CMR criteria
are positive. These include:
- Early Gd enhancement ratio equal to or greater than 4.0;
- regional or global T2 signal intensity ratio equal to or greater than 2.0;
- at least one focus of late enhancement.
2. LV function
- Ejection fraction,
- LVEDV,
- LVESV,
- LVEDVI,
- LVESVI,
- Stroke volume,
- Cardiac index,
- End-systolic wall stress
3. Quality of life will be quantified by a standardized questionnaire
Study Design Patients referred for a CMR study at the Stephenson Cardiovascular MR Centre
for suspected myocarditis will be screened. Patients with CMR-derived evidence for
myocarditis (i.e. at least two positive Lake Louise Criteria in at least one CMR scan during
the clinically acute phase of the disease) will be considered "myocarditis-positive".
As a control group, patients referred for suspected myocarditis but not fulfilling the
diagnostic CMR criteria for myocarditis and with normal systolic LV function. Both groups
will receive the same standard protocol as per the Consensus Group recommendations.
Follow-up will be performed between 4 and 8 weeks after the initial episode and at 1 year.
Data will include CMR results and quality of life assessment as quantified by a standardized
questionnaire.
Subjects
Recruitment
1. Inpatients identified by study nurses in collaboration with supervising cardiologists
2. Outpatients in Cardiology clinics Imaging protocol
All CMR imaging will be performed on a 1.5T MRI system (Avanto®, Siemens Medical Solutions,
Erlangen, Germany), with the use of a 32-channel cardiac phased array coil for functional
and late enhancement images and the body coil for T2-weighted images and early Gd
enhancement images. The protocol will be performed as follows:
- Left ventricular function Steady-state free precession (SSFP) gradient echo sequence
Six rotational long axis views, with each slice thickness of 10mm, and zero spacing in
between slices will be performed to cover the entire left ventricle.
- T2 weighted imaging Short TI inversion recovery (STIR) spin echo sequence Three short
axis slices will be obtained at basal, mid, and apical regions. Each slice will be 15mm
thick.
At this point, gadolinium-DTPA will be injected intravenously.
- Early enhancement imaging T1-weighted turbo spin echo sequence Three short axis slices
will be obtained at basal, mid, and apical regions before and immediately after (over 4
minutes) administration of 0.1ml/kgBW Gd-DTPA. Each slice is 10mm thick, and the
acquisition is T1-weighted and free-breathing. If image quality is insufficient in
short axis views, axial slices will be acquired.
- Late enhancement imaging Inversion-recovery prepared gradient echo sequences with
individual determination of inversion time according to maximal suppression of
myocardial signal, a stack of short axis views and a set of rotational long axis views
will be acquired 10 minutes after Gd-DTPA infusion. All of the left ventricle will be
covered in short-axis slices.
