Supplementary Methods
Fractional Flow Reserve versus Angiography in Guiding Management to
Optimise Outcomes in Non-ST-Segment Elevation Myocardial
Infarction: The British Heart Foundation FAMOUS–NSTEMI
randomised trial.
This document includes the Statistical Analysis Plan, and the Data and Safety
Monitoring Committee and Clinical Event Committee charters
Clinical trial registration numbers: NCT01764334 and ISRCTN97489534
1
Index
Supplementary Methods ................................................................................................................. 3
Statistical Analysis Plan ................................................................................................................ 18
Data and Safety Monitoring Committee Charter .......................................................................... 24
Trial Steering Committee (TSC) .................................................................................................. 35
Clinical Event Committee (CEC) Adjudication Charter .............................................................. 42
2
Supplementary Methods
Setting
Screening, enrolment, and data collection were performed in 6 UK hospitals: West of
Scotland Heart and Lung Centre, Golden Jubilee National Hospital, Glasgow, UK; University
Hospital Southampton, Southampton, UK; Hairmyres Hospital, East Kilbride, UK; Royal
Blackburn Hospital, Blackburn, UK; Freeman Hospital, Newcastle, UK; City Hospitals
Sunderland NHS Foundation Trust, Sunderland, UK.
Standard care of NSTEMI patients in the National Health Service
The participating hospitals adhere to current guidelines for optimal medical therapy(1,3) and
optimal revascularisation(1-3). Oral dual anti-platelet therapy and other secondary prevention
therapies were recommended in all participants once the diagnosis of NSTEMI had been
confirmed. Intravenous nitrate therapy was recommended for patients whose symptoms were
not initially controlled by oral anti-ischaemic drug therapy.
In this study, a diseased artery was defined as an epicardial artery with one or more lesions ≥
30% of the reference vessel diameter and amenable to PCI or CABG. An angiographically
significant artery was defined as an artery with one or more lesions ≥ 50% of the reference
vessel diameter. A left main stenosis of 50% and an epicardial coronary stenosis >70% are
usually taken to be obstructive lesions for which revascularization should be considered(1,2).
In contemporary practice, FFR is only measured in a minority of patients (<10% of patients
overall(22, 24)) and is not standard care as per clinical guidelines1,2. Patients who were
considered candidates for CABG were discussed at the Multidisciplinary Heart Team
meeting in each centre. In the angiography-guided group, the FFR data were not disclosed at
3
this meeting. If staged PCI was planned then the second procedure was recommended to take
place during the index hospitalisation.
The radial artery is the standard route for invasive angiography and PCI in our hospitals and
the radial artery was used according to operator and patient preference. Arterial blood
pressure and the ECG were monitored in the Cardiac Catheter Laboratory and cardiology
ward. Drug eluting or bare metal stents were used according to operator judgement and in
line with clinical guidelines.9 After the index invasive procedure was completed the patients
returned to the cardiology ward and were treated with optimal secondary prevention
measures.2
Screening and Registry patients
Patients who gave informed consent but who are not randomised were included in a registry.
The reasons for exclusion from the trial after consent but before randomisation (e.g. coronary
angiogram findings) and inclusion in the registry were prospectively recorded. Age and sex
were recorded in all of the registry participants, and other clinical data were collected
wherever possible.
Health status and frailty
Health-related quality of life (HRQoL; EuroQol 5-Dimensions 3-Level (EQ-5D-3L)25 was
assessed at baseline and again at 6 and 12 months. The participants were interviewed by the
research nurses and provided responses for the EQ-5D-3L questionnaire and EQ visual
analog scale (EQ-VAS). The EQ-5D-3L questionnaire comprises 5 dimensions: mobility,
self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 3
levels: no problems, some problems, extreme problems. The EQ-VAS records the
respondent’s self-rated health on a vertical, visual analogue scale where the outcomes are
labelled ‘Best imaginable health state’ and ‘Worst imaginable health state’. This information
4
can be used as a quantitative measure of health outcome as judged by the individual
respondents.
Frailty was assessed using the Canadian Study of Health and Aging (CSHA) Clinical Frailty
Scale.35
1 Very fit – robust, active, energetic, well motivated and fit; these people commonly exercise
regularly and are in the most fit group for their age
2 Well – without active disease, but less fit than people in category 1.
3 Well, with treated co-morbid disease – disease symptoms are well controlled compared
with those in category 4.
4 Apparently vulnerable – although not frankly dependent, these people commonly complain
of being “slowed up” or have disease symptoms.
5 Mildly frail – with limited dependence on others for instrumental activities of daily living.
6 Moderately frail – help is needed with both instrumental and non-instrumental activities of
daily living.
7 Severely frail – completely dependent on others for the activities of daily living, or
terminally ill.
These scores were summarised into 3 groups: Well (scores 1-3), Vulnerable (score 4) and
Frail (scores 5 - 7).
ECG analysis
A 12 lead electrocardiogram (ECG) was obtained in all participants following admission to
hospital. The ECGs were recorded at 100 Hz and 25 mm/s with an amplitude of 10.0
mm/mV. The ECGs were de-identified, scanned and sent to the lead site for central analysis.
5
A physician (M.L.) who was blind to treatment group assignment analysed the ECGs for
evidence of ischaemia.31M.L. had been trained in the University of Glasgow ECG Core
Laboratory that is certified to ISO 9001: 2008 standards as a UKAS Accredited Organisation.
The ECG criteria for ischaemia were ST-segment depression ≥ 0.1 mV in two contiguous
lead. Global ischaemia was taken to represent ≥6 leads with ST depression, maximally in V4
and with accompanying T-wave inversion in these leads. Transient ST-segment elevation was
taken to represent new ST elevation at the J point in two contiguous leads (≥0.1 mV in all
leads other than leads V2–V3 where ≥0.2 mV in men ≥40 years; ≥0.25 mV in women <40
years).The criteria were similar to those used in the TIMACS trial.31
Biochemical assessment of infarct size
Troponin I or T were measured as a biochemical measure of infarct size. Blood samples were
obtained on admission to hospital before enrolment, at the start of the procedure and 12 - 24
hours afterwards. Different troponin assays were used in each hospital. Troponin T (Elecsys
Troponin T, Roche) was measured in patients treated in the Golden Jubilee National Hospital,
Hairmyres Hospital, Freeman Hospital and Sunderland City Hospital. A troponin T
concentration of 14.0 pg/ml corresponds to the 99th percentile of a reference population for
this assay. Troponin I (Abbott Architect) was measured in patients admitted to acute hospitals
in Glasgow. The upper limit of normal for this assay is 0.04 µg/L. In the Royal Blackburn
Hospital, troponin I was measured with the high-sensitivity Siemens assay and the upper limit
of normal for this assay was < 30 ng/L. In Southampton University Hospital, troponin I was
measured (Beckman Coulter Dxi 800) and the upper limit of normal was 0.07 µg/L.
Catheter laboratory study protocol
Once the coronary angiogram has been obtained, the cardiologist will assess whether or not
the patient is eligible to be randomized based on angiographic criteria (Table 1).
6
The main angiographic inclusion criterion is the presence of one or more non-critical
coronary stenoses ≥30% severity which are associated with (1) normal coronary blood flow
(i.e. TIMI grade III), (2) amenable to revascularization by PCI or CABG and (3) FFR
measurement is feasible and may have diagnostic value (Table 1). A minimum stenosis
severity of 30% is adopted for FFR measurement in our study because visual assessment of
the angiogram may underestimate stenosis severity. Inclusion of a more severe stenosis (e.g.
>90% severity) is permissible provided the cardiologist believes FFR has the potential to
influence the treatment decision based on coronary and patient characteristics. Left main stem
disease is included. The pressure wire (Certus, St Jude Medical, Uppsala) will be used in all
patients to provide an FFR value across all coronary narrowings ≥30% severity as
appropriate. Our aim is to maximize inclusion of eligible patients to minimize selection bias.
Assessment of the coronary angiogram and recording of the initial treatment decision
Once the coronary angiogram has been obtained, the cardiologist will report the severity of
all coronary lesions as greater or less than 70% of the reference vessel diameter (50% for left
main) based on visual interpretation of the angiogram and in line with usual care. The
cardiologist will then establish an intended treatment plan based on all of the available
clinical information and the angiogram findings. The cardiologist's interpretation of the
diagnostic angiogram and the treatment plan will then be recorded at that time in the catheter
laboratory. Therefore, the initial treatment decision will be established before randomization
or treatment group assignment is known and before the pressure wire is passed into the
coronary arteries. Therefore, no FFR measurements will be acquired before randomisation.
Randomisation
Once the coronary angiographic findings and treatment plan have been recorded and if in the
opinion of the treating cardiologist the patient remains eligible to continue in the study,
7
randomization will then be performed. Randomisation will take place immediately in the
catheter laboratory using a web-based computer randomisation tool provided by the
independent Clinical Trials Unit. The randomisation sequence was created using the method
of randomized permuted blocks.
Patients who had consented but were ineligible on angiographic criteria will be entered into a
registry.
FFR measurement
Myocardial FFR measurement
FFR is the ratio of distal coronary pressure to aortic pressure measured during coronary
hyperaemia(5-10). According to eligibility criteria in the protocol (Table 1), FFR should be
measured in all coronary arteries with one or more stenoses ≥30% of the reference vessel
diameter based on visual assessment of the angiogram, with normal coronary blood flow
(TIMI grade III) and in the opinion of the attending cardiologist FFR measurement will be
feasible and may have diagnostic value. Left main stem disease is included and the upper
limit for left main stenosis severity is 80%. In order to facilitate the inclusion of patients with
complex disease, an FFR of 0.5 can be assigned without requirement to pass the pressure
wire in occluded arteries, left main lesions >80% and critical severe epicardial coronary
lesions (e.g. >90% severity) in which the cardiologist believes FFR has no diagnostic value.
This approach is intended to facilitate and maximise the inclusion of all eligible patients.
FFR will be measured according to best practice as described in the investigator guideline.
The cardiologist should pass the pressure wire across the target coronary stenosis. The
pressure wire (Certus, St Jude Medical, Uppsala) is similar to the guidewires that are
normally used in PCI except that the wire has a pressure-sensitive sensor 3 cm from its distal
tip. The pressure wire will be calibrated initially to ensure standardized measurements and
8
when positioned at the distal end of the guide catheter the pressure wire recording will be
equalized with the aortic pressure. The wire is then passed into the coronary artery of interest
and advanced at least 6 cm distal to the coronary stenosis using standard techniques. Once the
marker is appropriately positioned and after an initial 2 minute rest period, an intravenous
infusion of adenosine (140 /kg/min – 210 /kg/min) via a central vein or large antecubital
vein is started to establish coronary hyperaemia. Typical changes in blood pressure (i.e. fall
in systolic pressure >10%), heart rate (i.e. rise in heart rate >20%) and symptoms will be
recorded prospectively to confirm a hemodynamic response to adenosine during a period of
at least 2 minutes. When there is an inadequate response with the standard dose of adenosine
(140 /kg/min) then the dose can be increased up to 210 mcg/kg/min in order to best ensure
maximal hyperaemia. If intravenous adenosine is not tolerated then intracoronary adenosine
could be administered or FFR will be not be recorded and this will be noted in the Case
Report Form. Our protocol has been developed according to previous studies on the
hemodynamic response to intravenous adenosine when used for stress testing.
FFR-guided group: FFR will be measured by the cardiologist immediately after
randomization and the FFR result will used to guide treatment decisions based on a threshold
of 0.80. An FFR ≤ 0.80 should result in a treatment decision for revascularization by PCI or
CABG combined with optimal medical therapy and an FFR>0.80 should result in treatment
with optimal medical therapy alone, in line with contemporary guidelines for optimal
secondary prevention drug therapies, cardiac rehabilitation and risk factor modification1. Any
changes in treatment following FFR disclosure compared to the initial treatment plan prior to
FFR disclosure will be recorded.
Angiography-guided group and blinding: In patients randomized to the angiography-guided
group, the RadiAnalyzer Xpress (St Jude Medical, Uppsala) will be turned out of view by the
research team such that it is impossible for the clinical team to see the pressure wire
9
recording. The pressure wire recording will not be displayed on any other monitor in the
catheter laboratory and the clinicians and patients will not know the results. When the
coronary pressure display is out of view of the clinical team, the cardiologist will then
measure FFR as described above, guided by the research staff who will monitor and record
the pressure wire data. Therefore, the patient and the clinical team responsible for the patient,
including the interventional cardiologists and nurses, will be blinded to the pressure wire
recording. Quality control checks, including assessments of equalized pressure recordings
and verification of symptoms and hemodynamic changes with intravenous adenosine, will be
conducted in the usual way, with the guidance of the unblinded research team. These steps
will be followed for all FFR measurements.
Trial Management
The trial was conducted in line with Guidelines for Good Clinical Practice (GCP) in Clinical
Trials29. Trial management included a Trial Management Group, an independent Clinical
Event Committee (CEC) and an independent Clinical Trials Unit. Day to day study activity
was coordinated by the Trial Management Group who was responsible to the Sponsor which
was responsible for overall governance and that the trial was conducted according to GCP
standards.29
Clinical events were assessed and validated by an independent CEC comprised of 3
consultant cardiologists from Aberdeen Royal Infirmary, Aberdeen, UK (Chair, Dr Andrew
Hannah). The CEC followed an agreed charter and the CEC were blinded to randomization
and treatment group assignment.
Resource use and costs during index hospitalisation
A table of resource use items as well as their unit costs are provided below. Resource use
related to material use, procedures received, hospitalisation and events. Trial results were
10
bootstrapped and unit costs were randomly sampled using Monte Carlo simulation. Mean
estimates and 95% credible intervals were reported.
Material use included: catheters, balloons, stents, and drugs. Procedures included: CABG, xrays, echocardiograms and intravascular ultrasounds. Hospitalization use included: days spent
in the Coronary Care Unit (CCU), Intensive Treatment Unit (ITU) and general ward as well
as catheterization laboratory time. Events included: severe bleeding, stroke and MI.
The use of a pressure wire in patients randomised to coronary angiography alone was
removed from the cost estimates as it was protocol driven. Instead, coronary guidewire use
was included.
Equipment costs were derived from National Procurement. Average drug dosages were
estimated using NICE guidance (www.evidence.nhs.uk) while unit costs were derived from
the British National Formulary (www.bnf.org). Procedure unit costs (except CABG) as well
as CCU and ITU unit costs were derived from the Golden Jubilee National Hospital.
Catheterization laboratory time (per hour) was derived from Information Services Division
Scotland27.
To estimate the general ward day cost, inpatient excess bed day costs were taken from the
NHS Reference Costs for acute or suspected myocardial infarction (Healthcare Resource
Group [HRG] code EB10Z).
The procedure cost of CABG (HRG EA14Z) was derived from the NHS Reference Costs26.
As CABG procedures all involve admission, it was necessary to remove the bed day cost
from the NHS referenced cost to avoid double counting and to isolate the procedure cost.
NHS reported an average 6.02 bed days; expert clinical opinion estimated the sequence of
bed days as follows: 1 day general ward, 1 day ICU, 2 days CCU and 2.02 days general ward.
11
Event costs were derived from NHS Reference Costs. The HRG code used for stroke was
AA22A and AA22B; for myocardial infarction, EB10Z. No patients experienced a severe
bleed and thus it was not included.
All costs are presented in 2014 pound sterling.
To incorporate uncertainty, trial results were bootstrapped with stratification by
randomization group. We used 10,000 resamples. Where costs were uncertain, they were
randomly sampled from gamma distributions using Monte Carlo simulation methods.
Confidence intervals were reported as the 2.5th and 97.5th percentiles of the bootstrapped
results. Two-sided p-values were calculated on the bootstrapped replicates. They represent
the probability of getting something more extreme than what was observed. This is calculated
as the proportion of replicates less than and greater than the observed mean cost difference:
𝑝=
̅ )+𝑠𝑢𝑚(𝑋 > 𝑋̅ +𝛿
̅)
𝑠𝑢𝑚(𝑋 < 𝑋̅ −𝛿
# 𝑟𝑒𝑝𝑙𝑖𝑐𝑎𝑡𝑒𝑠
,
X is a vector of bootstrapped mean cost differences, 𝑋̅ is the mean cost difference and 𝛿 ̅ is the
extreme value which is the absolute value of 𝑋̅. This method is analogous to a one-sample ttest on the bootstrap replicates of mean cost differences where 𝛿 ̅ is tested on the distribution
X.
Table 1. Unit costs used to estimate in-hospital costs.
Equipment costs:
Guiding catheter
Guidewire
Pressure wire
Adenosine vial
Balloon catheter
Drug eluting stent
Bare metal stent
Tirofiban (avg/patient)
Bivalirudin (avg/patient)
Mean
SE
Distribution
20
20
352
12
40
256
55
146
366
0
0
0
0
0
0
0
0
0
determ
determ
determ
determ
determ
determ
determ
determ
determ
Source
National Procurement
National Procurement
National Procurement
BNF; evidence.nhs.uk
National Procurement
National Procurement
National Procurement
BNF; evidence.nhs.uk
BNF; evidence.nhs.uk
12
Procedure costs:
CABG
Echocardiogram
Optical coherence
tomography
Intravascular ultrasound
Chest X-ray
5,041
128
1,020
626
51
408
gamma
gamma
gamma
NHS Reference Costs
540
18
216
7
gamma
gamma
Golden Jubilee National Hospital
Hospitalization costs:
Cath lab time (per hour)
Day in CCU
Day in ITU
Day in General Ward
1,681
1,492
2,288
303
301
239
915
34
gamma
gamma
gamma
gamma
ISD Scotland
Event costs:
Stroke
MI
2,709
1,492
258
151
gamma
gamma
NHS Reference Costs
Golden Jubilee National Hospital
Golden Jubilee National Hospital
Golden Jubilee National Hospital
Golden Jubilee National Hospital
Golden Jubilee National Hospital
NHS Reference Costs
NHS Reference Costs
Histograms of material costs and in-hospital costs by treatment arm are presented below.
13
Figure 1. Histogram of bootstrapped material costs by treatment arm. FFR=fractional flow
reserve. CA=coronary angiography alone.
14
Figure 2.
Histogram of bootstrapped inhospital costs by treatment arm. FFR=fractional flow reserve.
CA=coronary angiography alone.
Definition of adverse events
A comprehensive definition of adverse events and their adjudication is detailed in the Clinical
Event Committee Charter.
Adverse health outcomes are defined as 'death from any cause, cardiovascular death, nonfatal MI, unplanned hospitalisation for unstable angina, unplanned hospitalisation for heart
failure, unplanned hospitalisation for TIA or stroke, PCI, or CABG'
15
Further specifications of these events as clinical endpoints:
1) Major Adverse Cardiovascular Events (MACE) is the composite of 'cardiovascular
death, non-fatal MI, unplanned hospitalisation for TIA or stroke
PCI and CABG are adverse events but are not defined as 'major'.
2) Major Adverse Cardiac Events are defined as 'cardiac death, non-fatal MI or unplanned
hospitalisation for heart failure'
3) MI associated with revascularisation procedures (types 4 and 5) Third Universal
Definition of MI, Thygesen et al Eur Heart J 201222
Type 4a: Myocardial infarction related to percutaneous coronary intervention (PCI)
Myocardial infarction associated with PCI is arbitrarily defined by elevation of cardiac
troponin values >5 x 99th percentile URL in patients with normal baseline values ≤99th
percentile URL) or a rise of cardiac troponin values >20% if the baseline values are elevated
and are stable or falling. In addition, either (i) symptoms suggestive of myocardial ischaemia,
or (ii) new ischaemic ECG changes or new LBBB, or (iii) angiographic loss of patency of a
major coronary artery or a side branch or persistent slow or no-flow or embolisation, or (iv)
imaging demonstration of new loss of viable myocardium or new regional wall motion
abnormality are required.
Type 4b: Myocardial infarction related to stent thrombosis
Myocardial infarction associated with stent thrombosis is detected by coronary angiography
or autopsy in the setting of myocardial ischaemia and with a rise and/or fall of cardiac
biomarkers values with at least one value above the 99th percentile URL.
Type 5: Myocardial infarction related to coronary artery bypass graft
16
Myocardial infarction associated with CABG is arbitrarily defined by elevation of cardiac
biomarker values >10 x 99th percentile URL in patients with normal baseline cardiac
troponin values ≤ 99th percentile URL. In addition, either (i) new pathological Q waves or
new LBBB, or (ii) angiographic documented new graft or new native coronary artery
occlusion, or (iii) imaging evidence of new loss of viable myocardium or new regional wall
motion abnormality.
4) Contrast-induced nephropathy: is defined as either a greater than 25% increase of serum
creatinine or an absolute increase in serum creatinine of 0.5 mg/dL after a radiographic
examination using a contrast agent.23
5) Bleeding: is defined according to the ACUITY criteria:24 major bleed = intracranial or
intraocular bleeding; bleeding at the site of angiography requiring intervention; a hematoma
of 5 cm in diameter; a reduction in haemoglobin level of at least 4 g/dL in the absence of
overt bleeding or 3 g/dL with a source of bleeding; or transfusion. Non-major bleeding by
ACUITY criteria will not be recorded as SAEs (and so would not be reportable to the
sponsor) but would be recorded in the eCRF.
References
Please refer to the bibliography in the manuscript.
17
Statistical Analysis Plan
18
Fractional Flow Reserve versus Angiographically Guided Management to
Optimise Outcomes in Unstable Coronary Syndromes: a developmental clinical
study of management guided by coronary angiography combined with
Study Title:
fractional flow reserve (FFR) measurement versus management guided by
coronary angiography alone(standard care) in patients with non-ST elevation
MI
Short Title:
FAMOUS
IDs:
REC reference number: 11/S0703/6
Funded by:
BHF
Protocol Version:
1.5
SAVP Version:
1.0
Date:
13/09/2013
Signature
Prepared by:
Date
Dr Alex McConnachie
Assistant Director of Biostatistics
Robertson Centre for Biostatistics
University of Glasgow
Approved by:
Prof Ian Ford
Director
Robertson Centre for Biostatistics
University of Glasgow
Chief Investigator:
Prof Colin Berry
Professor of Cardiology
Institute of Cardiovascular and Medical Sciences
126 University Place
University of Glasgow
19
1. Introduction
1.1. STUDY BACKGROUND
Coronary fractional flow reserve (FFR) is the pressure drop across a narrowed coronary
artery. FFR is measured with a coronary 'pressure wire' which is very similar to the wire
normally used in coronary angiography and angioplasty. Use of the pressure wire in patients
with recent heart attack could improve decision-making and health outcomes.
1.2. STUDY OBJECTIVES
FAMOUS is a developmental study to gather pilot information about whether or not the
pressure wire might be useful.
1.3. STUDY DESIGN
Parallel group, randomised controlled trial.
1.4. SAMPLE SIZE AND POWER
With 161 subjects in each of 2 arms (FFR disclosed against non-disclosed), or 322 subjects
randomised in total, the study would have 90% power at a 5% level of significance to detect
an increase from about 15% being treated medically to 30%. We have assumed zero loss to
follow up since the primary outcome is measured during the initial procedure. Allowing for
any technical difficulties or loss of data at the time of the procedure the total sample size will
be 350 patients.
1.5. STUDY POPULATION
Consecutive stable NSTEMI patients who on clinical grounds might be candidates for either
PCI or CABG and who provide informed consent will be enrolled. Full details of study
inclusion and exclusion criteria are given in the study protocol.
1.6. STATISTICAL ANALYSIS PLAN (SAP)
1.6.1. SAP OBJECTIVES
The objective of this SAP is to describe the statistical analyses to be carried out for the final
analysis of the FAMOUS Study.
1.6.2. GENERAL PRINCIPLES
Data will be presented overall, and by randomised group. For each variable summarised, the
number of available values and the number of missing values will be given. Continuous
variables will be summarised as mean, standard deviation, median, quartiles and range.
Categorical variables will be summarised as number and percentage per category.
Estimates of intervention effects will be reported with 95% confidence intervals and p-values,
unless otherwise stated. P-values will not be adjusted for multiple comparisons.
Bootstrapping will use 10,000 resampled datasets. Baseline characteristics and safety
outcomes will not be statistically compared between randomised groups.
20
1.6.3. CURRENT PROTOCOL
The current study protocol at the time or writing is version 1.5, dated 19/11/2012. Future
amendments to the protocol will be reviewed for their impact on this SAP, which will be
updated only if necessary. If no changes are required to this SAP following future
amendments to the study protocol, this will be documented as part of the Robertson Centre
Change Impact Assessment processes.
1.6.4. SOFTWARE
Analyses will be carried out with R for Windows v3.0.0, SAS for Windows v9.2, or higher
versions of these programs.
1.7 Analysis
1.7. STUDY POPULATIONS
The numbers of patients randomised, and the numbers and percentages providing data at each
follow-up point will be presented. The number and percentage who withdrew from the study
will be presented, and the reasons for withdrawal summarised.
1.8. BASELINE CHARACTERISTICS
The following baseline characteristics will be summarised:
-
-
-
age (years), sex, ethnic group (white/other), smoking;
history of cardiac arrhythmia, history of treated hypercholesterolaemia, history of
hypertension, history of renal impairment, family history of CAD, diabetes mellitus,
objective evidence of ischaemia, previous diagnostic angiogram, previous PCI,
previous MI, history of congestive cardiac failure;
current CCS Angina class, current NYHA functional class, Killip class, GRACE
score, ejection fraction;
medications at the time of angiogram (aspirin, anti-platelet, statin, other lipid lowering
drug, beta blocker, calcium channel blocker, long acting nitrate, nicorandil, ACE
inhibitor, angiotensin receptor blocker, alpha blocker, diuretic, other cardiac
medication;
time from index event to procedure (<5 days or ≥5 days).
Vessels Affected (separate summaries to be provided for all vessels, culprit vessels only, nonculprit vessels only):
-
-
whether each vessel affected (RCA prox, RCA mid, RCA distal, PDA from RCA,
Post-lat from RCA, left main stem, LAD prox, LAD mid, LAD distal, 1st diagonal,
2nd diagonal, Cx prox, OM, Cx distal, Post-lat from Cx, PDA from Cx, Additional
OM, Intermediate);
the level of stenosis, and whether each vessel affected with severe stenosis (>70% or
>50% for the left main stem);
the FFR value, and whether each vessel affected with FFR <0.80;
number of vessels affected;
number of vessels affected with severe stenosis;
21
-
number of vessels affected with FFR <0.80;
maximum stenosis of affected vessels;
minimum FFR of affected vessels.
1.9. PRIMARY ANALYSIS
The primary outcome is the whether the treatment decision is medical management or
revascularisation. The difference in proportions allocated to medical management between
randomised groups will be presented with an exact 95% confidence interval and p-value.
The proportions allocated to each possible treatment will similarly be presented and
compared between randomised groups.
1.10. SECONDARY ANALYSES
For both randomised groups combined, scatterplots will be produced showing the FFR value
vs. the level of stenosis, overall and for culprit/non-culprit vessels separately. The rate of
discordance between FFR and visual assessment of coronary stenosis severity will be
presented.
Clinical event rates will be presented for each follow up assessment point and compared
between groups using the same methods as the primary outcome. Clinical events of interest
(as determined by the Clinical Events Committee) will be:
1. Major Adverse Cardiovascular Events (MACE) – the composite of cardiovascular
death, non-fatal MI, unplanned hospitalisation for TIA or stroke;
2. Major Adverse Cardiac Events – cardiac death, non-fatal MI or unplanned
hospitalisation for heart failure;
3. Death from any cause.
Event types 1-3 will also be presented as the number of events per 100 person years, and
Kaplan-Meier plots will be presented, comparing randomised groups, with hazard ratios,
confidence intervals and p-values derived from Cox proportional hazards regression models.
These regression models will then be extended to investigate the predictive ability of FFR
results, level of stenosis and other baseline characteristics. ROC plots will be produced to
show the discriminatory ability of FFR in relation to each clinical event type, on its own and
in addition to other risk factors.
Quality of Life, represented by the EQ-5D health utility score will be summarised at each
time point and compared between randomised groups using two-sample t-tests. The QualityAdjusted Life Years (QALYs) accrued over 12 months will be estimated by the area under
the health utility curve. The mean QALY difference between groups will be estimated using
the method of recycled predictions from an appropriated generalised linear regression model
with bootstrapping.
1.11. ECONOMIC ANALYSES
The following cost-related variables will be summarised and compared between groups,
using bootstrap estimates of mean differences:
-
number of guiding catheters, ordinary guidewires and pressure wires;
22
-
number of adenosine doses;
number of balloon catheters;
number of drug eluting stents and bare metal stents;
use of (and type of) GP IIb/IIIa inhibitor;
use of bivalirudin;
use of IVUS and OCT;
use of intra-aortic balloon pump;
total radiation dose and contrast use;
total procedure time;
days on CCU, ITU and general ward;
number of echocardiograms, chest x-rays, invasive CV procedures and use of
ventilation.
1.12. SAFETY ANALYSES
The incidence of intra-procedural, post-procedural and in-hospital complications, as recorded
on the eCRF, will be summarised.
In addition, the Clinical Events Committee will adjudicate the occurrence of the following
safety outcomes:
1. MI associated with revascularisation procedures (Types 4 and 5, Third Universal
Definition of MI, Thygesen et al Eur Heart J 2012);
2. Contrast-induced nephropathy;
3. Bleeding.
These will be summarised and listed.
2. Document History
This is version 1.0 of the SAP for the final analysis of the FAMOUS Study, the initial
creation.
23
Data and Safety Monitoring Committee Charter
24
DSMC Charter
TITLE: A developmental clinical study of coronary FFR measurement in NSTEMI.
SHORT TITLE: FAMOUS NSTEMI.
Research Ethics Committee (REC) reference number: 11/S0703/6
Trial registration: NCT01764334 and ISRCTN97489534
Sponsor: National Waiting Times Board, Golden Jubilee National Hospital, Clydebank,
G81 4HX
Funder: British Heart Foundation project grant 2011, PG/11/55/28999
Supported by an unrestricted research grant from St Jude Medical UK Ltd for the
pressure wires to be used in this trial.
This charter has been prepared in line with the DAMOCLES Study Group
recommendations, Lancet 2005.
First draft August 2012; Final draft October 2012.
25
1.
Aims
Primary
1. To undertake a developmental / pilot study to determine whether or not pressure-wire
guided management is associated with a difference in the proportions of NSTEMI patients
allocated to medical care or coronary revascularisation at the time of coronary angiography.
Secondary
1) Is routine FFR measurement feasible in NSTEMI?
2) Do FFR values correspond to the angiographic severity of a stenosis when assessed
visually?
3) What is the quality of life in the NSTEMI study patients 12 months after entry to the study
(and does it differ between groups).
4) What are the in-hospital and clinical outcomes in the longer term in all patients?
5) Health economic sub-study: In NSTEMI patients amenable to coronary revascularisation
by either percutaneous coronary intervention (PCI) or coronary artery bypass surgery
(CABG), treatment-decisions based on detection of flow-limiting coronary artery stenoses
identified by guidewire-based coronary pressure measurement are associated with reduced
hospital costs compared to in NSTEMI patients who’s management has been based on visual
interpretation of the angiogram alone.
6) To perform cardiac MRI to provide imaging information into heart injury and repair.
26
2.
Flow chart
27
3.
Scope
The purpose of this document is to describe the roles and responsibilities of the independent
DMC for the FAMOUS-NSTEMI trial, including the timing of meetings, methods of
providing information to and from the DMC, frequency and format of meetings, statistical
issues and relationships with other committees.
28
4.
Roles and Responsibilities
To safeguard the interests of trial participants, assess the safety and efficacy of the
interventions during the trial, and monitor the overall conduct of the clinical trial.
Terms of reference
The DMC will receive and review the progress and accruing data of this trial and provide
advice on the conduct of the trial to the Trial Steering Committee.
Specific Roles of the DMC
Interim review of the trial’s progress including updated figures on recruitment, data quality,
and main outcomes and safety data.
Specific responsibilities are:

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monitor recruitment figures and losses to follow-up
monitor compliance with the protocol by participants and investigators
monitor organisation and implementation of trial protocol (the DMC should only
perform this role in the absence of other trial oversight committees)
monitor evidence for treatment differences in the main efficacy outcome measures
monitor evidence for treatment harm (e.g. toxicity data, SAEs, deaths)
decide whether to recommend that the trial continues to recruit participants or whether
recruitment should be terminated
suggest additional data analyses
advise on protocol modifications suggested by investigators or sponsors (e.g., to
inclusion criteria, trial endpoints, or sample size)
monitor compliance with previous DMC recommendations
consider the ethical implications of any recommendations made by the DMC
assess the impact and relevance of external evidence
DMC and the study protocol
All DMC members should have sight of the protocol/outline before agreeing to join
29
Before recruitment began, the trial had undergone review by the Funder (British Heart
Foundation project grant 2011, PG/11/55/28999), sponsor (R&D Office, National Waiting
Times Board), Trial Steering Committee and the research ethics committee (West of Scotland
Research Ethics Service, approved 2011; registration 11/S0703/6). The trial was also
reviewed by the R&D Group of the British Cardiovascular Intervention Society (June,
November 2010). DMC members should be independent and constructively critical of the
ongoing trial, but also supportive of aims and methods of the trial.
The independent DMC will meet on at least 3 occasions and will provide reports to the Trial
Steering Committee (TSC). The DMC will be the only group that has access to unblinded
data. The DMC will be comprised of 3 people: two cardiologists and a biostatistician (Chair).
The DMC will be organised by the Chief Investigator (CI) but attendance by investigators is
not allowed unless at the invitation of the DMC Chair.
The DMC will meet when all data are available for the safety assessments (in-hospital data
for the first 35 and 200 randomised patients) and when all data are available to close the
database. The trial statistician will provide a report to the DMC before each scheduled
meeting. If the DMC Chair recommends that the trial be stopped then the funding body will
be notified by the Chief Investigator. These operational criteria fulfil the terms of the MRC
Guidelines for Good Clinical Practice in Clinical Trials (1998).
Timing and milestones for progress in the study (Figure 2)
Progression during the study will require approval from the DMC after the 35th and 200th
randomised patients, as agreed with the DMC. The study will be subject to continuous review
by the TSC and DMC as appropriate and the hospital’s Governance Department.
30
5.
Background and current guidelines
Issues around the patient group
Acute non-ST elevation myocardial infarction (NSTEMI) is the commonest form of acute MI
and a leading global cause of premature morbidity and mortality. Multivessel coronary
disease affects around two thirds of NSTEMI patients and other co-morbidities, such as
peripheral vascular disease, are common.
Issues around the diagnostic methods and treatment decisions in usual care
A coronary angiogram is recommended in intermediate-high risk NSTEMI patients in order
to identify coronary artery narrowings (stenoses) and culprit coronary plaque rupture and so
identify patients who may benefit from coronary revascularisation. However, because the
coronary angiogram is interpreted visually judgements can only be subjective. Having said
that, the evidence-base supporting the current best practice is based on studies involving
visual interpretation of the coronary angiogram. The treatment decisions include medical
therapy, coronary balloon angioplasty with stenting or coronary artery bypass surgery.
Whether or not use of FFR may influence treatment decisions or clincial outcomes in
NSTEMI patients is unknown. Consequently there is an urgent need to assess and validate
new strategies for the management of intermediate-high risk NSTEMI patients.
Guidewire-based coronary pressure measurement (ie FFR) can identify obstructive CAD in
patients with stable angina (and potentially unstable coronary disease too). The FFR index is
measured by a conventional coronary wire with a pressure sensor on its distal tip. When the
wire is passed across a coronary narrowing, the pressure drop across the narrowing is
indicative of the clinical significance of this stenosis, including its severity, the likelihood of
myocardial ischaemia, and the risk of adverse outcome. As mentioned above, studies have
highlighted the value of FFR in guiding stenting and enhancing outcomes in patients with
31
stable, chronic CAD. However, the potential prognostic and diagnostic benefit of guidewirebased coronary pressure measurement to inform the management and treatment of acute
CAD, as observed in NSTEMI patients, has not yet been validated.
Current guidelines of the European Society of Cardiology, summary statements:
PCI guidelines, European Heart Journal 2010
5.4 When non-invasive stress imaging is contraindicated, non-diagnostic, or unavailable, the
measurement of FFR or coronary flow reserve is helpful
7.4 Multiple angiographically significant non-culprit stenoses or lesions whose severity is
difficult to assess, liberal use of FFR measurement is recommended (N.B: no level of
evidence is ascribed to this statement).
NSTE-ACS guidelines, European Heart Journal 2011
3.2.4 In lesions whose severity is difficult to assess, intravascular ultrasound or fractional
flow reserve (FFR) measurements carried out >5 days after the index event are useful in order
to decide on the treatment strategy (reference, FAME NEJM, 2009)
Regulatory considerations: The RADI-St Jude pressure wire (Certus, TM) is CE-marked.
The Chief Investigator is not aware of any regulatory issues around use of the technology in
this trial.
Guidelines of the American Heart Association / American College of Cardiology:
AHA/ACC Focused update guidelines for PCI in 2011 (Circulation 2011; 124: e574-e651)
32
5.4.1 FFR is recommended in stable ischaemic heart disease (Class IIa Recommendation)
No mention is made of FFR in PCI patients with a history of unstable coronary disease.
AHA/ACC Focused update guidelines for unstable angina/NSTEMI in 2011 (Circulation
2011; 124: e574-e651)
FFR is not mentioned in this guideline or in the guideline for 2007
6.
Membership
DMC member agreement: while there is no formal contract, the DMC members should agree
to membership and the contents of this charter. The DMC members should complete a
‘competing interests’ form, Appendix A.
The DMC members for this trial are:
Professor John Norrie (Chair), Statistician
Dr Saqib Chowdhary, Consultant Cardiologist, South Manchester University Hospitals
Professor Andrew Clark, University of Hull
Professor Norrie is Director of the Health Services Research Unit, University of Aberdeen,
and he has substantial experience in trial methodology, including DMC work. Dr Chowdhary
is a Consultant Interventional Cardiologist in Wythenshawe Hospital, Manchester. Drs
Chowdhary is an interventional cardiologist with substantial experience in using the coronary
pressure wire in ordinary clinical practice and in clinical research. Both are active members
of the British Cardiovascular Intervention Society. Professor Clark is a Consultant
Cardiologist with an interest in heart failure.
33
7.
Meetings
Meetings may be face-to-face or by teleconference. Meetings may be ‘open’ or ‘closed’. A
closed meeting includes the DMC members only. An open meeting may be attended by the
Chief Investigator, sponsor representative, funder, or regulator as appropriate. The DMC,
lead by the Chair, will decide on whether a meeting should be open or closed.
8.
Study reports and documents
The DMC will be provided with a study report prior to meeting, wherever possible 1 – 2
weeks before the date of the meeting. The report will be coordinated by the trial statistician.
The DMC members should store the papers safely after each meeting so they may check the
next report against them. After the trial is reported, the DMC members should destroy all
interim reports.
Trial documentation and procedures.
Open sessions: Accumulating information relating to recruitment and data quality (e.g., data
return rates, protocol compliance) will be presented. Safety data may be presented and total
numbers of events for the primary outcome measure and other outcome measures may be
presented, at the discretion of the DMC
Closed sessions: In addition to all the material available in the open session, the closed
session material will include efficacy and safety data by treatment group. The DMC will not
be blinded to treatment assignment.
Pre-specified interim analyses: DMC members do not have the right to share confidential
information with anyone outside the analysis DMC, including the Chief Investigator.
34
External evidence (e.g. systematic reviews, new publications): Circulation of new
information, such as a scientific publication relevant to the trial, is the responsibility of the
Chief Investigator and not the DMC.
9.
Responsibilities
Chair - should have experience of serving on DMCs and should be able to facilitate and
summarise discussion. The Chair should provide the DMC reports.
Statistician - should have independent statistical expertise.
DMC members - should have experience in clinical and invasive cardiology.
Chief investigator - The C.I. may be asked, and should be available, to attend open sessions
of the DMC meeting. The other TMG members will not usually be expected to attend but can
attend open sessions when necessary.
Confidentiality
The DMC members must respect confidentiality with respect to the study information they
receive or discuss.
Minutes of DMC meetings
The DMC should keep minutes of their meetings and these documents should be confidential.
Responsibilities of other committees
Trial Steering Committee (TSC) – The TSC will include the Lead Applicant/Chief
Investigator (Berry), a Cardiac Surgeon (Mr Geoff Berg), a senior Cardiologist (Professor
Oldroyd), and an independent expert Chair with experience in clinical trials (Dr Robert
35
Henderson, BCIS Council Member). The TSC will ensure overall trial supervision and that it
is conducted according to the Good Clinical Practice standards. The TSC will meet face-toface or by teleconference on a 1 – 2 monthly basis as appropriate. A TSC meeting will start
and close the study and action progress based on the safety analyses after randomisation of 35
(10%) and 200 (57%) patients, as agreed with the DMC.
Trial Management Group (TMG) ~ there will be a TMG for each hospital. The TMG will
include the Local Principal Investigator in each hospital, the research fellow and our Clinical
Research Nurses (CRNs). TMG members will be in day to day contact and will convene on at
least a monthly basis. The TMGs will be responsible to the Trial Steering Committee (TSC).
10.
DMC Decisions
Possible DMC recommendations could include:1. No action needed, trial continues as planned.
2. Stopping recruitment within a subgroup
3. Extending recruitment (based on actual control arm response rates being different to
predicted rather than on emerging differences) or extending follow-up.
4. Sanctioning and/or proposing protocol changes
Statistical methods
Decision-making
The DMC will form a view based on consideration of the study data and reports. Decisions
will be by majority (i.e. since the DMC consists of 3 members, agreement between at least
two of the members is needed to make a decision). Expression of final opinion may be by
vote at the discretion of the DMC Chair, although details of the vote may not be included in
the report to the TSC as such information may inappropriately convey information about the
36
state of the trial data. The role of the Chair is to summarise discussion and encourage
consensus. Every effort should be made to achieve a unanimous decision.
Communication of decisions: The DMC usually reports its recommendations in writing to the
Trial Steering Committee or sponsor’s representative. The Chair of the TSC may decide to
convene a meeting on receipt of the DMC report. If the trial is to continue largely unchanged
then it is often useful for the report from the DMC to include a summary paragraph suitable
for trial promotion purposes.
Conditions for DMC to be quorate
Effort should be made for all members to attend and that the DMC members identify a date
that is suitable for all members to participate. For a face-to-face meeting, members who
cannot attend in person should be encouraged to attend by teleconference. If, at short notice,
any DMC members cannot attend at all then the DMC may still meet if at least one
statistician and one clinician, including the Chair (unless otherwise agreed), will be present. If
the DMC is considering recommending major action after such a meeting the DMC Chair
should talk with the absent members as soon after the meeting as possible to check they
agree. If they do not, a further teleconference should be arranged with the full DMC.
For DMC members who cannot attend the meeting, he should provide written comments to
the DMC chair on the study report that is circulated to DMC members before the meeting. If
a member does not attend a meeting, it should be ensured that the member is available for the
next meeting. If a member does not attend a second meeting, they should be asked if they
wish to remain part of the DMC. If a member does not attend a third meeting, they should be
replaced.
37
Weighting for safety and efficacy endpoints
In general terms, the Safety Endpoints that will be monitored include:
death from any cause, cardiovascular death, non-fatal MI, unplanned hospitalisation for
unstable angina, unplanned hospitalisation for heart failure, unplanned hospitalisation for TIA
or stroke, PCI, CABG; procedure related MI, contrast nephropathy, coronary dissection.
Safety
In general, safety endpoints that will be monitored will include:
1) Major Adverse Cardiovascular Events (MACCE) is the composite of 'cardiovascular
death, non-fatal MI, unplanned hospitalisation for TIA or stroke’.
PCI and CABG are adverse events that should be reviewed but are not defined as 'major'.
2) 'Major Adverse Cardiac Events (MACE) are defined as 'death from any cause, non-fatal
MI or unplanned hospitalisation for heart failure'
3) Procedure-related MI in line with the Third Universal Definition of MI (Thygesen et al
Eur Heart J 2012).
4) Contrast-induced nephropathy: is defined as either a greater than 25% increase of serum
creatinine or an absolute increase in serum creatinine of 0.5 mg/dL after a radiographic
examination using a contrast agent. (Barrett BJ N Engl J Med 2006)
5) Bleeding: is defined according to the ACUITY criteria: major bleed = intracranial or
intraocular bleeding; bleeding at the site of angiography requiring intervention; a hematoma
of 5 cm in diameter; a reduction in haemoglobin level of at least 4 g/dL in the absence of
overt bleeding or 3 g/dL with a source of bleeding; or transfusion. Non-major bleeding by
38
ACUITY criteria will not be recorded as SAEs (and so would not be reportable to the
sponsor) but would be recorded in the eCRF.
6) Coronary guidewire dissection rates (in line with DSMB meeting of June 2012)
Efficacy
Efficacy endpoints are the adverse cardiac events listed as secondary endpoints in the trial
protocol and death. At the time of the pre-specified analyses, the events rates would be
assessed for a between group difference or no difference such that with continued recruitment
these observations would be unlikely to change.
11.
Reporting
The DMC report will be finalised and sent by the DMC Chair to the Chair of the TSC and PI,
ideally within 3 weeks of the meeting.
Minutes of the DMC meeting are not required on the basis that the meeting report provides a
representative account of the conclusions and reasons around the recommendations. DMC
members are encouraged to keep personal notes.
If the DMC has serious problems or concerns with the TSC decision a meeting of these
groups should be held. The information to be shown would depend upon the action proposed
and the DMC’s concerns. Depending on the reason for the disagreement confidential data
will often have to be revealed to all those attending such a meeting. The meeting should be
chaired by a senior individual associated with the trial (e.g. sponsor’s representative) or an
external expert who is not directly involved with the trial.
39
12.
After the trial
DMC report at the end of the trial: The DMC should provide a final report to the TSC at the
end of the trial.
Publication of results: At the end of the trial there may be a meeting to allow the DMC to
discuss the final data with principal trial investigators/sponsors and give advice about data
interpretation. The DMC may wish to see a statement that the trial results will be published in
a correct and timely manner.
Information about DMC members in publications for the trial: DMC members should be
named and their affiliations listed in the main report, unless they explicitly request otherwise.
A brief summary of the timings and conclusions of DMC meetings should be included in the
body of this paper. The DMC should have the opportunity to read and comment on any
publications before submission. Study information should be kept confidential by DMC
members during the study and up till publication of the results. After the publication of the
study results, the DMC may publically discuss issues from their involvement in the trial,
ideally following prior discussion with the TSC Chair and CI.
40
Appendix
Potential competing interests of DMC members
DMC members should disclose potential competing interests to the Trial Sponsor. Such
interests could include:
41
Clinical Event Committee (CEC) Adjudication Charter
Version Date: January 2013
42
BACKGROUND
INTRODUCTION: In patients with acute non-ST elevation myocardial infarction
(NSTEMI) coronary arteriography is usually recommended however visual interpretation of
the coronary angiogram is subjective. A complementary diagnostic approach involves
measuring the pressure drop across a coronary stenosis (fractional flow reserve, FFR) with a
pressure-sensitive guidewire which is very similar to the wire normally used in coronary
angiography and angioplasty. The pressure wire is approved and routinely used in stable
angina patients but not in patients with recent heart attack because of a lack of evidence.
ACTIVE HYPOTHESIS: Use of the pressure wire in patients with recent NSTEMI could
improve decision-making and health outcomes. Rationale: In order to demonstrate whether
this could be the case a large clinical trial would be needed. However, before such a trial
could be done, a 'developmental' study is needed first in order to gather 'pilot' information
about whether or not the pressure wire might be useful.
DESIGN: A prospective multi-centre randomised controlled trial in 350 NSTEMI patients
with ≥1 coronary stenosis ≥30% severity (threshold for FFR measurement). Patients will be
randomized immediately after coronary angiography to the FFR-guided group or
angiography-guided group (FFR measured, not disclosed). All patients will then undergo
FFR measurement in all vessels with a coronary stenosis ≥30% severity. FFR will be
measured in culprit and non-culprit lesions in all patients. FFR will be disclosed to guide
treatment in the FFR guided-group but not disclosed in the 'angiography-guided' group. In the
FFR-guided group, an FFR>0.80 will be an indication for medical therapy whereas an
FFR≤0.80 will be an indication for revascularization by percutaneous coronary intervention
(PCI) or coronary artery bypass surgery (CABG), as appropriate. The primary endpoint is the
between-group difference in the proportion of patients allocated to medical management
compared to revascularization. A key secondary composite outcome is the occurrence of
43
cardiac death or hospitalisation for myocardial infarction or heart failure. Other secondary
outcomes include quality of life, hospitalisation for unstable angina, coronary
revascularisation or stroke, and healthcare costs. Exploratory analyses will also assess the
relationships between FFR and angiographic lesion characteristics (severity, culprit status).
The minimum and average follow-up periods for the primary analysis are 6 and 18 months
respectively. A secondary analysis with longer term follow-up (minimum 3 years) is planned.
IMPORTANCE: This developmental clinical trial will address the feasibility of FFR
measurement in NSTEMI and the influence of FFR disclosure on treatment decisions and
health and economic outcomes. The FAMOUS NSTEMI trial is registered at NCT01764334
and ISRCTN97489534.
Rationale for a clinical event adjudication committee
An independent Clinical Event Committee (CEC) is proposed to review deaths (due to any
cause) and specifically cardiovascular events of interest. At a high level, such events of
interest will include death of any cause, non-fatal acute myocardial infarction, non-fatal
stroke, hospitalisation due to unstable angina, hospitalisation due to heart failure and
coronary revascularisation procedures (i.e. percutaneous coronary intervention, coronary
artery bypass grafting). The revascularisation procedures will not be considered to be major
adverse events of interest but will be reviewed by the CEC to ensure that events of interest
(e.g. acute myocardial infarction, hospitalisation for unstable angina) have not been missed.
44
(Note: CV events are not a primary endpoint in the FAMOUS NSTEMI study, but instead
will be analyzed separately within the context of standard safety analyses for the study
reports and submission).
The CEC will review cases of interest to determine if they meet accepted diagnostic criteria.
Causality assessments will not be made by the CEC, nor will the committee possess
governance authority. The CEC will be blinded regarding any information relating to the
randomisation group.
All deaths and pre-specified major adverse cardiovascular events (i.e. “MACE”-type events)
will be prospectively collected by investigators and classified independently by the CEC.
Details on these pre-specified events are listed in section 4.
As noted above, events of interest will be identified primarily by the investigator who will
use an eCRF checkbox to mark all adverse and serious events. As a conservative measure,
safety data will also be reviewed by the Pharmacovigilance team in the Robertson Centre for
Biostatistics, an NIHR-approved Trials Unit, in order to identify any cases which may have
been missed by the investigators (for further details, please refer to Safety Monitoring in the
protocol).
All organizational and operational aspects of the CEC will be administered and directed by
the National Waiting Times Board (NWTB) which is the Sponsor.
Objective
The purpose of this document is to delineate the roles, responsibilities and procedures in
regards to the adjudication of cardiovascular events occurring in the FAMOUS NSTEMI
trial.
45
Composition and responsibilities of the CEC
The CEC consists of at least 3 cardiovascular physicians who have expertise in the diagnosis
and treatment of cardiovascular disorders and in the medical aspects of clinical trials:
CEC Member
Affiliation
Dr Andrew Hannah (Consultant
Dept. Cardiology, Aberdeen Royal
Cardiologist), Chairman
Infirmary, Aberdeen, UK.
Dr Malcolm Metcalfe
Dept. Cardiology, Aberdeen Royal
Infirmary, Aberdeen, UK.
Dr Andrew Stewart
Dept. Cardiology, Aberdeen Royal
Infirmary, Aberdeen, UK.
In the event that a CEC member is unable to continue participation, the CEC Chairman will
recommend a replacement to the Sponsor. The Sponsor has the final decision as to the
replacement. CEC members may not participate in the study as principal or co-investigators,
nor can they participate in the medical care of a patient in the study.
The CEC Chairman (Dr Andrew Hannah) will be responsible for:
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Acting as the primary liaison between the CEC and the Sponsor
Selection of CEC members
The overall conduct of the CEC
Participating in the development of CEC Charter
Submission of General Event Forms and Death Event Forms to Sponsor and Clinical
Trial Unit
46
CEC members will be responsible for:
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Reading and understanding the content of FAMOUS NSTEMI trial (NCT01764334)
Reviewing the relevant de-identified clinical data about a subject identified as having
experienced a suspected event of interest requiring adjudication
Adjudicating pre-specified clinical events of interest (see section 4) in keeping with
the study definitions outlined in section 5.
Completion of General Event Forms and Death Event Forms
Timely submission of event adjudication decisions
Communicating with the CEC Chairman about needs when necessary
Attending scheduled CEC meetings throughout the study
Completion of confidentiality form
CEC Coordinator
The CEC is assisted by a CEC coordinator (Dr Jamie Layland, BHF Cardiovascular Research
Centre, University of Glasgow; jamie.layland@nhs.net) who is a registered physician based
in the University of Glasgow and Golden Jubilee National Hospital and who has considerable
previous experience in the conduct of cardiovascular clinic trial activity.
The CEC coordinator will:
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Assist with preparation for the CEC meetings
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Enter the classification verdicts reached at CEC meetings into the database
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Interact with the CEC Chair as appropriate
Events to be reviewed
The adverse events which are pre-specified outcomes in this trial are listed in Appendix A.
3.1 Deaths
47
The CEC will review all reported deaths and classify the cause of death according to the
following schema:

Non-cardiovascular
A definite non-cardiovascular cause of death must be identified.

Cardiovascular (CV)
 Death due to acute myocardial infarction
 Death due to stroke
 Sudden cardiac death
 Other CV death (e.g. heart failure, pulmonary embolism, cardiovascular
procedure-related)
Undetermined cause of death (i.e. cause of death unknown)

3.2
Non-fatal cardiovascular events
The CEC will review and adjudicate the following reported non-fatal cardiovascular events:

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Acute myocardial infarction
Hospitalisation for unstable angina/other angina*/chest pain*
Stroke/TIA/Other cerebrovascular events (i.e. subdural/extradural haemorrhage)**
Heart failure requiring hospitalisation
Coronary revascularisation procedures (i.e. percutaneous coronary intervention,
coronary artery bypass grafting)***
Renal failure (>25% rise in creatinine from baseline or an absolute increase in serum
creatinine of 0.5 mg/dL (44 µmol/L) after a radiographic examination using a contrast
agent (Barrett NEJM 2006;354:379-86)
Bleeding according to the ACUITY criteria (Stone Am Heart J 2004;148:764-75)
Note: Other non-fatal cardiovascular events will not routinely be reviewed by the CEC. These
events will be reviewed by trained and qualified clinical research staff in the Golden Jubilee
National Hospital to ensure that potential cardiovascular events requiring adjudication are not
missed. If the review suggests that a potential cardiovascular event requiring adjudication
may have been missed, further information will be requested, as required and, if necessary,
the event will be allocated to the CEC for adjudication.
48
*Hospitalisation for other angina or for chest pain are not study events of interest but such
events will be reviewed by the CEC to ensure that acute myocardial infarction or
hospitalisation for unstable angina events have not been missed.
**Other cerebrovascular events (subdural haemorrhage, extradural haemorrhage) are not
study events of interest but will be reviewed by the CEC to ensure that stroke events have not
been missed.
***Coronary revascularisation procedures (i.e. percutaneous coronary intervention, coronary
artery bypass grafting) are not study events of interest but will be reviewed by the CEC to
sure that study events of interest (e.g. acute myocardial infarction, hospitalisation for unstable
angina) have not been missed.
Event definitions
For those event-types requiring adjudication, each event will usually be adjudicated
on the basis of strict application of the endpoint definitions below. However, the clinical
likelihood that a suspected event has occurred will be individually assessed even in the
absence of fulfilment of all of the criteria specified in the event-definition, recognizing that
information may at times be difficult to interpret (e.g. the exact measurement of ECG
changes may be imprecise) or unavailable. The CEC will discuss such cases at a full CEC
meeting and adjudicate them using their clinical expertise and the totality of the evidence
before arriving at a classification decision that is based on full consensus.
Overall, event definitions should align with the "Standardised definitions for
endpoint events in cardiovascular trials' Hicks KA et al May 2011 and the "Third Universal
Definition of Myocardial Infarction" (Thygesen et al Eur Heart J 2012) for diagnosis of
myocardial infarction.
49
4.1
Deaths
In cases where a patient experiences an event and later dies due to that event, the event
causing death and the death will be considered as separate events only if they are separated by
a change in calendar day. If the event causing death and the death occur on the same
calendar day, death will be the only event classified.
A separate 'Death event form' should be completed.
4.1.1 Cardiovascular deaths
Cardiovascular death includes death resulting from an acute myocardial infarction, sudden
cardiac death, death due to heart failure, death due to stroke and death due to other
cardiovascular causes as follows:
Death due to Acute Myocardial Infarction refers to a death usually occurring up to 30 days
after a documented acute myocardial infarction (verified either by the diagnostic criteria
outlined below for acute myocardial infarction, above, or by autopsy findings showing recent
myocardial infarction or recent coronary thrombus) due to the myocardial infarction or its
immediate consequences (e.g. progressive heart failure) and where there is no conclusive
evidence of another cause of death.
If death occurs before biochemical confirmation of myocardial necrosis can be obtained,
adjudication should be based on clinical presentation and other (e.g. ECG, angiographic,
autopsy) evidence.
50
NOTE: This category will include sudden cardiac death, involving cardiac arrest, often with
symptoms suggestive of myocardial ischaemia, and accompanied by presumably new ST
elevation*, or new left bundle branch block*, or evidence of fresh thrombus in a coronary
artery by coronary angiography and/or at autopsy, but death occurring before blood samples
could be obtained, or at a time before the appearance of cardiac biomarkers in the blood (i.e.
myocardial infarction Type 3 – see section 4.2.1, below).
*If ECG tracings are not available for review, the CEC may adjudicate on the basis of
reported new ECG changes that have been clearly documented in the case records or in the
case report form.
Death resulting from a procedure to treat an acute myocardial infarction [percutaneous
coronary intervention (PCI), coronary artery bypass graft surgery (CABG)], or to treat a
complication resulting from acute myocardial infarction, should also be considered death due
to acute myocardial infarction.
Death resulting from a procedure to treat myocardial ischaemia (angina) or death due to an
acute myocardial infarction that occurs as a direct consequence of a cardiovascular
investigation/procedure/operation that was not undertaken to treat an acute myocardial
infarction or its complications should be considered as a death due to other cardiovascular
causes.
Sudden Cardiac Death refers to a death that occurs unexpectedly in a previously stable
patient. The cause of death should not be due to another adjudicated cause (e.g. acute
myocardial infarction Type 3 – see section 4.2.1 below).
The following deaths should be included.
a. Death witnessed and instantaneous without new or worsening symptoms
51
b. Death witnessed within 60 minutes of the onset of new or worsening symptoms unless a
cause other than cardiac is obvious.
c. Death witnessed and attributed to an identified arrhythmia (e.g., captured on an ECG
recording, witnessed on a monitor), or unwitnessed but found on implantable cardioverterdefibrillator review.
d. Death in patients resuscitated from cardiac arrest in the absence of pre-existing circulatory
failure or other causes of death, including acute myocardial infarction, and who die (without
identification of a non-cardiac aetiology) within 72 hours or without gaining consciousness;
similar patients who died during an attempted resuscitation.
e. Type 3 MI ~ Cardiac death with symptoms suggestive of myocardial ischaemia and
presumed new ischaemic ECG changes or new LBBB, but death occurring before blood
samples could be obtained, before cardiac biomarker could rise, or in rare cases cardiac
biomarkers were not collected.
Unwitnessed death without any other cause of death identified (information regarding the
patient’s clinical status in the 24 hours preceding death should be provided, if available)
Death due to Heart Failure refers to a death occurring in the context of clinically worsening
symptoms and/or signs of heart failure without evidence of another cause of death (e.g. acute
myocardial infarction).
Death due to heart failure should include sudden death occurring during an admission for
worsening heart failure as well as death from progressive heart failure or cardiogenic shock
following implantation of a mechanical assist device.
New or worsening signs and/or symptoms of heart failure include any of the following:
52
a. New or increasing symptoms and/or signs of heart failure requiring the initiation of, or an
increase in, treatment directed at heart failure or occurring in a patient already receiving
maximal therapy for heart failure
Note: If time does not allow for the initiation of, or an increase in, treatment directed at heart failure
or if the circumstances were such that doing so would have been inappropriate (e.g. patient refusal),
the CEC will adjudicate on clinical presentation and, if available, investigative evidence.
b. Heart failure symptoms or signs requiring continuous intravenous therapy (i.e. at least once
daily bolus administration or continuous maintenance infusion)
c. Confinement to bed predominantly due to heart failure symptoms.
d. Pulmonary oedema sufficient to cause tachypnoea and distress not occurring in the context
of an acute myocardial infarction, worsening renal function (that is not wholly explained by
worsening heart failure/cardiac function) or as the consequence of an arrhythmia occurring in
the absence of worsening heart failure.
e. Cardiogenic shock not occurring in the context of an acute myocardial infarction or as the
consequence of an arrhythmia occurring in the absence of worsening heart failure.
Cardiogenic shock is defined as systolic blood pressure (SBP) < 90 mm Hg for
greater than 1 hour, not responsive to fluid resuscitation and/or heart rate correction,
and felt to be secondary to cardiac dysfunction and associated with at least one of the
following signs of hypoperfusion:




Cool, clammy skin or
Oliguria (urine output < 30 mL/hour) or
Altered sensorium or
Cardiac index < 2.2 L/min/m2
53
Cardiogenic shock can also be defined if SBP < 90 mm Hg and increases to ≥ 90 mm
Hg in less than 1 hour with positive inotropic or vasopressor agents alone and/or with
mechanical support.
Death due to Stroke refers to death after a documented stroke (verified by the diagnostic
criteria outlined below for stroke or by typical post mortem findings) that is either a direct
consequence of the stroke or a complication of the stroke and where there is no conclusive
evidence of another cause of death.
NOTE: In cases of early death where confirmation of the diagnosis cannot be obtained, the
CEC may adjudicate based on clinical presentation alone.
Death due to a stroke reported to occur as a direct consequence of a cardiovascular
investigation/procedure/operation will be classified as death due to other cardiovascular
cause.
Death due to subdural or extradural haemorrhages will be adjudicated (based on clinical signs
and symptoms as well as neuroimaging and/or autopsy) and classified separately.
Death due to Other Cardiovascular Causes refers to a cardiovascular death not included in
the above categories [e.g. pulmonary embolism, cardiovascular intervention (other than one
performed to treat an acute myocardial infarction or a complication of an acute myocardial
infarction – see definition of death due to myocardial infarction, above), aortic aneurysm
rupture, or peripheral arterial disease]. Mortal complications of cardiac surgery or nonsurgical revascularization should be classified as cardiovascular deaths.
54
4.1.2 Non-cardiovascular deaths
A non-cardiovascular death is defined as any death that is not thought to be due to a
cardiovascular cause. There should be unequivocal and documented evidence of a noncardiovascular cause of death.
Further sub-classification of non-cardiovascular death will be as follows:











Pulmonary
Renal
Gastrointestinal
Infection (includes sepsis)
Non-infectious (e.g., systemic inflammatory response syndrome (SIRS))
Malignancy
Haemorrhage, not intracranial
Accidental/Trauma
Suicide
Non-cardiovascular surgery
Other non-cardiovascular, specify: ________________
4.1.3 Undetermined cause of death
This refers to any death not attributable to one of the above categories of cardiovascular death
or to a non-cardiovascular cause (e.g. due to lack of information such as a case where the
only information available is “patient died”). It is expected that every effort will be made to
provide the adjudicating committee with enough information to attribute deaths to either a
cardiovascular or non-cardiovascular cause so that the use of this category is kept to a
minimal number of patients.
4.1.4 Non-fatal Cardiovascular Events
Date of onset
55
For purposes of classification, when classifying events that are a cause of hospitalisation, the
date of admission will be used as the onset date. In cases where the stated date of admission
differs from the date the patient first presented to hospital with the event (e.g. because of a
period of observation in an emergency department, medical assessment unit or equivalent),
the date of initial presentation to hospital will be used (provided that the patient had not been
discharged from hospital in the interim).
For events where an admission date is not applicable (or not available), the date of onset as
stated by the investigator will be used.
4.2.1 Acute myocardial infarction
Note on biomarker elevations:
For cardiac biomarkers, laboratories should report an upper reference limit (URL). If the 99th
percentile of the upper reference limit (URL) from the respective laboratory performing the
assay is not available, then the URL for myocardial necrosis from the laboratory should be
used. If the 99th percentile of the URL or the URL for myocardial necrosis is not available,
the MI decision limit for the particular laboratory should be used as the URL.
Diagnosis of spontaneous or PCI/CABG-related acute myocardial infarction:
A rise and/or fall of cardiac biomarkers (troponin or CK-MB) should usually be detected
wherever possible with at least one value above the upper reference limit (URL) together
with clinical evidence of new myocardial ischaemia with at least one of the following:
56
Clinical symptoms and/or signs consistent with new ischaemia
ECG evidence of acute myocardial ischaemia or new left bundle branch block (LBBB)
(Table, below).
Development of new pathological Q waves on the ECG (see Table 2, below)
Imaging evidence of new loss of viable myocardium or new regional wall motion
abnormality
Autopsy evidence of acute myocardial infarction
Specific clinical classification of different types of myocardial infarction Universal
Definition of Myocardial Infarction (Thygesen et al Eur Heart J 2012)
Myocardial infarctions will be clinically classified as:
Type 1
Spontaneous myocardial infarction related to ischaemia due to a primary coronary event such
as plaque erosion and/or rupture, fissuring, or dissection.
Type 2
Myocardial infarction secondary to ischaemia due to either increased oxygen demand or
decreased supply, e.g. coronary artery spasm, coronary embolism, anaemia, arrhythmias,
hypertension, or hypotension.
Type 3
Sudden unexpected cardiac death, including cardiac arrest, often with symptoms suggestive
of myocardial ischaemia, accompanied by presumably new ST elevation, or new LBBB, or
evidence of fresh thrombus in a coronary artery by angiography and/or at autopsy, but death
occurring before blood samples could be obtained, or at a time before the appearance of
cardiac biomarkers in the blood.
Type 4a: Myocardial infarction related to percutaneous coronary intervention (PCI)
57
Myocardial infarction associated with PCI is arbitrarily defined by elevation of cTn values >5
x 99th percentile URL in patients with normal baseline values (≤99th percentile URL) or a
rise of cTn values >20% if the baseline values are elevated and are stable or falling. In
addition, either (i) symptoms suggestive of myocardial ischaemia, or (ii) new ischaemic
ECG changes or new LBBB, or (iii) angiographic loss of patency of a major coronary artery
or a side branch or persistent slow or no-flow or embolisation, or (iv) imaging demonstration
of new loss of viable myocardium or new regional wall motion abnormality are required.
Type 4b: Myocardial infarction related to stent thrombosis
Myocardial infarction associated with stent thrombosis is detected by coronary angiography
or autopsy in the setting of myocardial ischaemia and with a rise and/or fall of cardiac
biomarkers values with at least one value above the 99th percentile URL.
Type 5: Myocardial infarction related to coronary artery bypass grafting (CABG)
Myocardial infarction associated with CABG is arbitrarily defined by elevation of cardiac
biomarker values >10 x 99th percentile URL in patients with normal baseline cTn values
(≤99th percentile URL). In addition, either (i) new pathological Q waves or new LBBB, or (ii)
angiographic documented new graft or new native coronary artery occlusion, or (iii) imaging
evidence of new loss of viable myocardium or new regional wall motion abnormality.
58
Table 1: ECG manifestations of acute myocardial ischaemia (in absence of left
ventricular hypertrophy and left bundle branch block)
ST elevation
New ST elevation at the J-point in two anatomically contiguous leads with the cut-off
points: ≥ 0.2 mV in men (> 0.25 mV in men < 40 years) or ≥ 0.15 mV in women in
leads V2-V3 and/or ≥ 0.1 mV in other leads.
ST depression and T wave changes
New horizontal or down-sloping ST depression ≥ 0.05 mV in two
contiguous leads; and/or new T wave inversion ≥ 0.1 mV in two contiguous
leads.
The above ECG criteria illustrate patterns consistent with myocardial ischaemia. In
patients with abnormal biomarkers, it is recognized that lesser ECG abnormalities may
represent an ischemic response and may be accepted under the category of abnormal ECG
findings.
59
Table 2: Pathological Q waves:

Any Q-wave in leads V2-V3 ≥ 0.02 seconds or QS complex in leads V2 and
V3

Q-wave ≥ 0.03 seconds and ≥ 0.1 mV deep or QS complex in leads I, II, aVL,
aVF, or V4-V6 in any two leads of a contiguous lead grouping (I, aVL, V6;
V4-V6; II, III, and aVF) a
aThe
same criteria are used for supplemental leads V7-V9, and for the Cabrera frontal
plane lead grouping.
4.2.2 Hospitalisation for unstable angina
For the diagnosis of hospitalisation due to unstable angina there should be
emergency/unplanned admission to a hospital setting (emergency room, observation or
inpatient unit) that results in at least one overnight stay (i.e. a date change) with fulfilment of
the following criteria:
There should be:
1. Cardiac ischaemic-type symptoms at rest (chest pain or equivalent) or an
accelerating pattern of angina (e.g. exercise-related ischaemic-type symptoms
increasing in frequency and/or severity, decreasing threshold for onset of
exercise related ischaemic type symptoms) but without the fulfilment of the
above diagnostic criteria for acute myocardial infarction.
and
60
2
The need for treatment with parenteral (intravenous, intra-arterial, buccal,
transcutaneous or subcutaneous) anti-ischemic/antithrombotic therapy and/or
coronary revascularization.
and
3a ECG manifestations of acute myocardial ischaemia (New ST-T changes
meeting the criteria for acute myocardial ischaemia - as outlined in Table 1,
section 5.2.1).
or
3b Angiographically significant coronary artery disease thought to be responsible
for the patient’s presentation. [If both invasive and CT angiographic imaging
of the coronary arteries were performed, the results of the invasive coronary
angiogram should take preference.]
and
4
The CEC should be satisfied that unstable angina was the primary reason for
hospitalisation.
4.2.3 Hospitalisation for other angina*
For the diagnosis of hospitalisation for other angina, there should be
emergency/unplanned admission to a hospital setting (emergency room,
observation or inpatient unit) that results in at least one overnight stay (i.e. a
date change) with fulfilment of the following criteria:
There should be:
61
1
Typical cardiac ischaemic-type symptoms but without the fulfilment of the
above diagnostic criteria for acute myocardial infarction or unstable angina.
and
2 The need for treatment with new or increased anti-anginal therapy (excluding
sublingual nitrate therapy).
and
3a
Investigations undertaken in view of the event (e.g. exercise ECG or stress
myocardial perfusion scan) showing evidence of reversible myocardial
ischaemia.
or
3b Coronary angiography showing angiographically significant coronary disease
thought to be responsible for the patient’s presentation. [If both invasive and
CT angiographic imaging of the coronary arteries were performed, the results
of the invasive coronary angiogram should take preference.]
and
4
The CEC should be satisfied that angina was the primary reason
hospitalisation.
4.2.4 Hospitalisation for other chest pain*
There should be:

Emergency/unplanned admission to a hospital setting (emergency room, observation or
inpatient unit) that results in at least one overnight stay i.e. a date change) due to chest
pain but where the definitions (above) of acute myocardial infarction, hospitalisation for
unstable angina or hospitalisation for other angina are not met.
62

The CEC should be satisfied that chest pain was the primary reason for hospitalisation.
*These events are not study cardiovascular events of interest but the definitions provided for
these events will be used by the CEC to categorise reported myocardial infarction, angina
and chest pain events that do not meet the study definition of acute myocardial infarction or
hospitalisation for unstable angina.
4.2.5 Stroke
Stroke is defined as an acute episode of neurological dysfunction caused by focal or global
brain, spinal cord, or retinal vascular injury.
A For the diagnosis of stroke, the following 4 criteria should usually be fulfilled:
1. Rapid onset* of a focal/global neurological deficit with at least one of the
following:








Change in level of consciousness
Hemiplegia
Hemiparesis
Numbness or sensory loss affecting one side of the body
Dysphasia/aphasia
Hemianopia (loss of half of the field of vision of one or both eyes)
Complete/partial loss of vision of one eye
Other new neurological sign(s)/symptom(s) consistent with stroke
*If the mode of onset is uncertain, a diagnosis of stroke may be made provided that
there is no plausible non-stroke cause for the clinical presentation.
2.
Duration of a focal/global neurological deficit > 24 hours
or
63
< 24 hours if
(i)
this is because of at least one of the following therapeutic interventions:
(a) pharmacologic i.e. thrombolytic drug administration.
(b) non-pharmacologic i.e. neurointerventional procedure (e.g.
intracranial angioplasty).
or
(ii)
brain imaging available clearly documenting a new haemorrhage or
infarct.
or
(iii)
the neurological deficit results in death
3. No other readily identifiable non-stroke cause for the clinical presentation (e.g.
brain tumour, hypoglycaemia, peripheral lesion).
4. Confirmation of the diagnosis by at least one of the following**:
a) neurology or neurosurgical specialist.
b) brain imaging procedure (at least one of the following):
(i)
CT scan.
(ii)
MRI scan.
(iii) cerebral vessel angiography.
c) lumbar puncture (i.e. spinal fluid analysis diagnostic of intracranial haemorrhage).
**If a stroke is reported but evidence of confirmation of the diagnosis by the methods
outlined above is absent, the event will be discussed at a full CEC meeting. In such
cases, the event may be adjudicated as a stroke on the basis of the clinical presentation
alone but full CEC consensus will be mandatory.
64
B
If the acute neurological deficit represents a worsening of a previous deficit, this
worsened deficit must have:
Persisted for more than one week
Or < one week if
(i)
this is because of at least one of the following therapeutic interventions:
(a) pharmacologic i.e. thrombolytic drug administration.
(b) non-pharmacologic i.e. neurointerventional procedure (e.g.
intracranial angioplasty).
or
(ii)
brain imaging available clearly documenting an appropriate new
CT/MRI finding.
or
(iii)
the neurological deficit results in death
Strokes will be further sub-classified as:

Ischaemic (non-hemorrhagic) stroke
(i.e. caused by an infarction of central nervous system tissue)
or

Hemorrhagic stroke***
65
(i.e. caused by nontraumatic intraparenchymal, intraventricular or
subarachnoid hemorrhage)
or

Stroke type (i.e. hemorrhagic or ischaemic) unknown (i.e. when
imaging/other investigations are unavailable or inconclusive).
***Subdural and extradural haemorrhages will be adjudicated (based on clinical signs and
symptoms as well as neuroimaging and/or autopsy) and classified separately by the CEC
4.2.6. Heart Failure requiring hospitalisation
For the diagnosis of heart failure requiring hospitalisation, there should be
emergency/unplanned admission to a hospital setting (emergency room, observation or
inpatient unit) that results in at least one overnight stay (i.e. a date change) with fulfilment of
the following criteria:
There should be:
- clinical manifestations of new or worsening heart failure including at least one of the
following:
New or worsening dyspnoea on exertion
New or worsening dyspnoea at rest
New or worsening fatigue/decreased exercise tolerance
New or worsening orthopnoea
New or worsening PND (paroxysmal nocturnal dyspnoea)
New or worsening lower limb or sacral oedema
New or worsening pulmonary crackles/crepitations
New or worsening elevation of JVP (jugular venous pressure)
New or worsening third heart sound or gallop rhythm
And
2 Investigative evidence of structural or functional heart disease (if available) with at
least one of the following:
66




Radiological evidence of pulmonary oedema/congestion or cardiomegaly.
Imaging ( e.g. echocardiography, cardiac magnetic resonance imaging,
radionuclide ventriculography) evidence of an abnormality (e.g. left
ventricular systolic dysfunction, significant valvular heart disease, left
ventricular hypertrophy).
Elevation of BNP or NT-proBNP levels.
Other investigative evidence of structural or functional heart disease (e.g.
evidence obtained from pulmonary artery catheterisation).
And
3
Need for new/increased therapy* specifically for the treatment of heart failure
including at least one of the following:

New or increased oral therapy for the treatment of heart failure
(See note on oral therapy, below)

Initiation of intravenous diuretic, inotrope, vasodilator or other recognised
intravenous heart failure treatment or uptitration of such intravenous therapy if
already receiving it
Mechanical or surgical intervention (e.g. mechanical or non-invasive ventilation,
mechanical circulatory support, heart transplantation, ventricular pacing to improve
cardiac function), or the use of ultrafiltration, hemofiltration, dialysis or other
mechanical or surgical intervention that is specifically directed at treatment of heart
failure.

Note on oral therapy: In general, for an event to qualify as heart failure requiring
hospitalisation on the basis of oral heart failure therapy (i.e. in cases where none of
the non-pharmacological treatment modalities listed above have been utilised), the
new or increased oral therapy should include oral diuretics. However, in special
cases, other new or increased oral therapy (e.g. hydralazine/long acting nitrate,
aldosterone antagonist) may be accepted provided that the adjudication committee is
satisfied that:
a) the new or increased oral therapy was primarily directed at treating clinical
manifestations of new or worsening heart failure (rather than, for example, initiation
or uptitration of heart failure therapy as part of the routine optimisation of medical
therapy)
67
and
b) the totality of the evidence indicates that heart failure, rather than any other disease
process, was the primary cause of the clinical presentation.
*If time does not allow for the initiation of, or an increase in, treatment directed at heart
failure or if the circumstances were such that doing so would have been inappropriate (e.g.
patient refusal), the CEC will adjudicate on clinical presentation and, if available,
investigative evidence.
And
4
The CEC should be satisfied that heart failure was the primary disease process
accounting for the clinical presentation.
Adjudication process
A flowchart of the overall CEC adjudication process is shown in Appendix B.
For the first 10 reported events requiring adjudication, the events will be reviewed at a CEC
meeting with at least 3 members present. The purpose of this committee review will be to
ensure that all committee members are applying the endpoint definitions as described in this
charter and that all members are aligned in their applications of the definitions to the
classifications of events. In this review of the initial 10 events, full consensus will be required
for each final classification decision, as noted in section 6.4 below.
6.1
Event identification
The FAMOUS NSTEMI study will use paper-based and electronic data capture (EDC).
Those events requiring review by the CEC (see section 4) will be reported by the Investigator
68
via the EDC (electronic data capture) system. The Investigator will complete all required
Case Report Form pages for the event type.
As a conservative measure, safety data will also be reviewed on behalf of the sponsor by the
Pharmacovigilance Office of the NIHR Clinical Trials Unit (Robertson Centre for
Biostatistics, University of Glasgow).
6.2
Phase 1 CEC review
The CEC members will receive electronic notification that they have events ready for
adjudication. The date of dispatch to the CEC members will be recorded electronically.
With the exception of possible cerebrovascular events (see note below), each suspected event
package will be reviewed independently by 2 of the CEC members with an interest in
cardiology (i.e. a pair selected from the CEC). Pairs will be rotated automatically in a
manner that ensures that events are distributed to the members on an even basis. The pair
will enter their adjudication decisions into the General Event Classification Form. For each
event where the reviewers have agreed on a classification, the event is deemed classified.
Disagreements will be highlighted for adjudication at a scheduled CEC meeting (“Phase 2
CEC review” - see section 6.4). The decision to defer classification until a scheduled CEC
meeting will be logged.
Note: All possible cerebrovascular events will be classified by consensus at a CEC meeting
with all members (ideally including a physician with experience in cerebrovascular medicine)
present.
69
6.3
Incomplete event data
If, having reviewed the event data pertaining to an event, a CEC member deems that the
information provided is insufficient for the purposes of event adjudication, an electronic
request for further information detailing the information required will be made. The date of
request will be recorded electronically and the event will be classified as not
adjudicated/pending additional information. When new information becomes available, it will
be sent in a deidentified form to the CEC Chair. It is expected that both the details of the
original request for information and the new or updated information received will be clearly
flagged to the adjudicators within the event package.
In instances where it is confirmed that efforts to obtain requested information have been
unsuccessful (e.g. because the study site has indicated that the information is not available),
classification of the event will be deferred pending its discussion at a scheduled CEC meeting
(see section 6.4).
6.3 Phase 2 CEC review
The CEC will convene at regular intervals throughout the study. In general, these will be
face- to- face meetings, however, if for some reason a face- to- face meeting is not possible, a
meeting by teleconference may substitute.
The frequency of meetings depends on the quantity of clinical events received by the CEC
but it is planned that they will be scheduled to occur once quarterly. These may be cancelled
if there is no business for discussion or cases to be reviewed by full committee.
70
The primary objective of CEC meetings is the “Phase 2 review” and classification of those
events for which a final classification decision has not been achieved by the Phase 1 review
process already outlined above and to review and classify cerebrovascular events that have
been reported. Phase 2 review of an event constitutes the discussion and adjudication of the
event by the CEC as a group.
For cerebrovascular events, as well as all other events, the final classification decision will be
decided on the basis of full CEC consensus.
If the CEC are unable to arrive at a classification verdict for an event because of incomplete
or inadequate information and it is felt that such information may be obtainable (i.e. the study
site has not indicated that the information required is unavailable), the Chairman will detail
the precise information/documentation that is needed to achieve classification and this will be
requested using the process described above.
The event will be tabled and reviewed
subsequently at a CEC meeting when the information requested has been made available (or,
when, despite best efforts, it is confirmed that the information will not be obtainable).
6.4
Adjudication timelines
The CEC will make every effort to review events and to enter their classification decisions
onto the General Event Classification Forms within 2 to 4 weeks from the time that the event
data is received by the CEC members, although this may vary slightly. To facilitate the
prompt adjudication of events, it is expected that adverse event data received by the CEC will
be as clean and complete as possible and that any CEC data-queries are resolved in a timely
fashion.
71
Every effort will be made to ensure that scheduled CEC meetings take place at least
quarterly. The frequency of CEC meetings may be increased if required; provided that there
is mutual agreement between the Sponsor and the CEC before any change is made.
If necessary, the above timelines may be amended as the study progresses, if the CEC and the
other relevant parties agree on a new schedule of event turn-around time.
6.5
Interactions with Sponsor and Communications
The CEC will make every reasonable effort to answer Sponsor queries and provide medical
advice if requested, as well as any reasonable request for a periodic review meeting.
The primary point of contact between the CEC and Sponsor will be the trial PI (Professor
Colin Berry email: colin.berry@glasgow.ac.uk).
Clinical data to be provided
The trial management team (including Prof Berry, Dr Layland, Ms Anna O'Donnell RN, Ms
Joanne Kelly RN) will provide event data for each potential cardiovascular event requiring
adjudication to the CEC. These events will also be provided to the Pharmacovigilance Office
of the NIHR Trials Unit. The CEC will be blinded to all patient randomization schedules. For
studies that are open label, such as the FAMOUS NSTEMI study, treatment allocations will
be blinded by prior to documents being submitted for CEC review and classifications.
Data to be included for event classification will include:
72


Subject study identification number and event details
Adverse event form

On request: Relevant de-identified CRF data (including any relevant
event-specific CRFs e.g. the myocardial infarction/hospitalisation for
unstable angina/other angina/chest pain event form).
Supportive source documentation as required
Baseline and subsequent scheduled ECGs obtained during study
participation.
All clinical data would be de-identified.



De-identified Source Documentation
The following source documents (if available) will be provided to the CEC on request to
facilitate the review and adjudication of events:
Death
●
●
●
●
Hospital Discharge Summary/Death Summary
Autopsy Report
Death Certificate
Admission History & Physical (if applicable)
Acute Myocardial Infarction/Hospitalisation for Unstable Angina/Other Angina/Chest
Pain
● Hospital Discharge Summary
● ECGs
● Pre-Randomisation/Screening
● Baseline (prior to event but post-randomization)
● During Event
● Post-Event
● Relevant Procedure/Operation Reports
● Relevant Laboratory Reports (e.g. that document the cardiac enzyme/marker
measurements provided – peak values and pre-procedure and post-procedure values,
where applicable)
● Reports for other investigations taken:
● PCI Report
73
● CABG Report
● Coronary Angiography Report
● Echocardiogram Report
● Exercise ECG Report
● Stress Myocardial Perfusion Scan Report
● Other investigation report undertaken to test for presence of reversible
myocardial ischaemia
● Admission History & Physical
Stroke/TIA/Other cerebrovascular events
● Hospital Discharge Summary
● Neurology Consultation Report(s)
● Reports for other investigations undertaken:
● CT Brain Scan Report
● MRI Brain Scan Report
● Cerebral Angiography Report
● Lumbar Puncture Report
● Admission History & Physical
Heart Failure requiring hospitalisation
●
●
●
●
●
●
Hospital Discharge Summary
Chest X-Ray Report
Prescription Sheets/Medication Administration Records
Echocardiogram Report
Relevant Laboratory Reports (e.g. for peak BNP/NT-proBNP)
Reports for other investigations undertaken:
● Cardiac Magnetic Resonance Imaging
● Radionuclide Ventriculogram Scan
● Pulmonary Artery Catherization
● Admission History & Physical
Coronary revascularisation procedure
●
●
●
●
Hospital Discharge Summary
Relevant Procedure/Operation Reports
Troponin results
ECGs
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Quality assurance
For the purposes of quality assurance, 10 % of all events initially classified may be subject to
review by the CEC again. If there are any discrepancies between the initial and the
subsequent adjudication decisions, the Chairman and the Sponsor will discuss the steps
necessary to ensure reconciliation and resolution of the issue.
75
Approvals
The following CEC and Sponsor representatives have approved this Charter.
Name
Dr. Andrew Hannah
Title
Signature
Date
Chairperson,
CEC
Dr. Malcolm
Member, CEC
Metcalfe
Dr. Andrew Stewart
Member, CEC
Dr.
Member, CEC
Dr.
Sponsor
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APPENDIX A:
Definition of adverse events
1) Major Adverse Cardiovascular Events (MACE) is the composite of 'cardiovascular death,
non-fatal MI, unplanned hospitalization for TIA or stroke.'
2) 'Major Adverse Cardiac Events' are defined as 'cardiac death, or unplanned hospitalization
for MI or heart failure.'
PCI and CABG are non-major adverse events.
3) Procedure-related MI is defined according to the Third Universal Definition of Myocardial
Infarction (Type 4 for PCI and Type 5 for CABG).
4) Contrast-induced nephropathy: is defined as either a greater than 25% increase of serum
creatinine or an absolute increase in serum creatinine of 0.5 mg/dL after a radiographic
examination using a contrast agent.
5) Bleeding: is defined according to the ACUITY criteria: major bleed = intracranial or
intraocular bleeding; bleeding at the site of angiography requiring intervention; a hematoma
of 5 cm in diameter; a reduction in haemoglobin level of at least 4 g/dL in the absence of
overt bleeding or 3 g/dL with a source of bleeding; or transfusion.
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ADJUDICATION PROCESS FLOWCHARTS
Cardiovascular Event Flowchart:
Event Identified by
Investigator
Allocated for Independent Review by 2 CV-EAC Cardiology
Physicians
(The above excludes cerebrovascular events which will not be
allocated for independent review by 2 cardiology physicians.
Instead, these events will be classified by consensus at a CVEAC meeting with the stroke physician present.)
NO
Required/
Sufficient
Data
Additional Data
Requested
YES
Adjudication Decision Entered
NO
Event Discussed
at CV-EAC
Meeting
Reviewers
Agree
YES
Event Classified
Classification
Reached By
Consensus
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