Official Title Verification of the Safety of Early Discharge (Within 72 Hours) in Low Risk Patients After Acute ST-segment Elevation Myocardial Infarction Treated With Primary Percutaneous Coronary Intervention. Open Randomized Study.
Phase: NA
Conditions: Coronary Artery Disease, Acute Myocardial Infarction With ST-segment Elevation, Primary Percutaneous Coronary Intervention, Early Discharge
Sponsor: Kamil Novobílský

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Verification of the safety of early discharge (within 72 hours) in
low risk patients after acute ST-segment elevation myocardial
infarction treated with primary percutaneous coronary
intervention. Open randomized study.
(NCT02023983)
Study protocol
Protocol date:   August 24, 2013
Study sponsor, principal investigator:
                       Dr. Kamil Novobílský
                       Department of Cardiology
                       Municipal hospital Ostrava
                       Nemocniční 20
                       728 80  Ostrava
                       Czech Republic
                       +420 59 619 2660
                    k.novobilsky@mnof.cz

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Introduction:
Within past decades we can observe the clear trend towards the shortening of the
hospital stay in pateints admitted with the diagnosis of myocardial infarction
with ST segment elevations (STEMI).
The current Guidelines of European Society of Cardiology for the management
of acute myocardial infarction with ST-segment elevation, released in 2012,
state, that in the selected patients may be considered (class of recommendation
IIb) early discharge (after approximately 72 hours), if adequate follow-up is
arranged.
Level of evidence of cited recommendation is B, i.e. it is based on data, derived
from a single randomized clinical trial or large non-randomized studies.
The overview of literature on this topic shows non-uniform  mtehodology of
these works and heterogenous features of studied populations (3 – 63% fulfilled
criteria for early discharge!)
In the PAMI II study tle low risk was defined as following: age <70 years, left
ventricule ejection fraction >45%, one- or two-vessel disease, successful
percutaneous coronary intervention (PCI) and no persistent arrythmias.
In Czech Republic the issue of early discharge was investigated in PRASGUE 5
study (Jirmar et al., 2008), which after pilot phase randomized 56 low risk
probands with STEMI, discharged even the next day after successful PCI. The
strict inclusion criteria (fulfilled only 3% patients with acute STEMI) included
age < 75 years, optimal result of primary PCI, on-vessel disease, left ventrikule
ejection fraction > 40%, place of residence < 20km, exclusion criteria involved
patients after Q-MI, haemodynamically or rythmically instable, with recurrent
chest pain or clinical/laboratory findings requiring additional evaluation.
Followed endpoints were death, reinfarction, stroke, instable angina pectoris,
repeat target vessel revascularization, local groin complications requiring
treatment and left ventricule ejection fraction within 30 days. This study also
showed, that very early discharge in clearly defined group of patients is safe,
there was just one rehospitalization due to non-cardiac cause in the group of 37
paients, discharged the next day after MI, there was no other serious event in
study  population.
By the verification of safety of early discharge this study wants to confirm the
applicability of presented  conclusions even in the regular clinical practice in our
circumstances.

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References:
1. Newby LK, Califf RM, Guerci A, et al. Early discharge in the thrombolytic
      era: an analysis of criteria for uncomplicated infarction from the global
      utilization of streptokinase and t-PA for occluded coronary arteries
      (GUSTO) trial. J Am Coll Cardiol. 1996;27(Suppl 3):625–632
  2. Steg PG, James SK, Atar D, Badano LP, Blomstrom-Lundqvist C, Borger
     MA, Di Mario C, Dickstein K, Ducrocq G, Fernandez-Aviles F, Gershlick
     AH, Giannuzzi P, Halvorsen S, Huber K, Peter P,  Kastrati A, Knuuti J,
     Lenzen MJ,  Mahaffey KW, Valgimigli M, Van’t Hof  A, Widimsky P,
     Zahger D. Guidelines for the management of acute myocardial infarction in
     patients presenting with ST-segment elevation: The Task Force on the
     management of  ST-segment elevation acute myocardial infarction of the
     European Society of  Cardiology. Eur Heart J  2012; 33:2569-2619
  3. Thygesen K, Alpert JS, White HD, Jaffe AS. Third universal definition of
      myocardial infarction. Eur Heart J 2012; 33: 2551–2567.
  4. Grines CL, Marsalese DL, Brodie BR et al. Safety and costeffectiveness
     of early discharge after primary angioplasty in low risk patients with acute
     myocardial infarction. J Am Coll Cardiol 1998; 31: 967–72.
  5. Jirmář R, Widimský P, Čapek J, et al. Next day discharge after successful
     primary angioplasty for acute ST elevation myocardial infarction. An open
     randomized study „Prague-5“.  Int Heart J 2008; 49:653–659.
  6. Noman A, Zaman AG, Schechter C, et al. Early discharge after primary
      percutaneous coronary intervention for ST-elevation myocardial infarction.
      Eur Heart J Acute Cardiovasc Care. 2013; Epub ahead of print.
  7. Newby LK, Califf RM, Guerci A, et al. Early discharge in the thrombolytic
     era: an analysis of criteria for uncomplicated infarction from the global
     utilization of streptokinase and t-PA for occluded coronary arteries (GUSTO)
     trial. J Am Coll Cardiol. 1996;27(Suppl 3):625–632
  8. Topol EJ, Burek K, O´Neil WW,  et al. A Randomized Controlled Trial of
      Hospital Discharge Three Days after Myocardial Infarction in the Era of
      Reperfusion. N Engl J Med 1988; 318:1083-1088
  9. Jones D, Rathod KS, Howard JP, et al. Safety and feasibility of hospital
      discharge 2 days following primary percutaneous intervention for ST-
      segment elevation myocardial infarction. Heart. 2012;98(23):1722-7
10. Yip HK, Wu CJ, Chang HW, Hang CL, Wang CP, Yang CH, et al. The
      feasibility and safety of early discharge for low risk patients with acute
      myocardial infarction after successful direct percutaneous coronary
      intervention. Jpn Heart J. 2003; 44(1): 41-9
11. Slany J. Is SHORT hospital treatment safe for patients with acute
      myocardial infarction? Eur Heart J (2000) 21 (12): 964-966.

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Design of clinical investigation
Clinical, prospective, monocentric, randomized, open study
Study objective:
The aim of the study is to prove
-
that early discharge (within 72 hours) in selected group of patients with
low risk of follow-up complications after myocardial infarction with
elevations of ST segment, treated with primary percutaneous coronary
intervention, is feasible and safe
-
that early discharge is „non-inferior“ in comparison with the group of
patients, discharged in a standard way accordingly with present practice
and physician´s decision (usually 4th-7th day), thus it is not associated
with higher incidence of complications in 30th and 90th day after
myocardial infarction
Impact on other therapeutic measures:
The study hes no impact on the subsequent care, which is commonly provided to
all patietnts after myocardial infarction: it does not concern the medication,
control paraclinical tests and regular clinical controls, scheduled by the
attending physician.

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Study population:
All subjects enrolled in the study.
Study eligibility:
All inclusion and no exclusion criteria of enrolled patients mus be fulfiled.
Incluison criteria:
·
Signed informed consent
·
STEMI treated with successful primary PCI within 12 h of the symptom
onset (TIMI flow 3 in infarct-related artery)
·
Age ≥18  and ≤ 75 years
·
Left ventricular ejection fraction ≥  45%
·
One- or two-vessel disease ((stenosis of major epicardial artery ≥ 70%)
·
No symptoms of residual ischaemia
·
Haemodynamical and rhythmical stability ((Killip class I, no arrytmia
requiring treatment occurring > 2 hours after PCI)
·
·
Absence of comorbidities, requiring continuation of hospitalization
·
Absence of contraindication for dual antiplatelet treatment or need for
anticoagulation
·
Supposed cooperation, adherence to medical measures and social
background
Exclusion kriteria:
·
Symptoms of residual ischemia
·
Significant comorbidities or abnormalities in paraclinical tests, requiring
additional evaluation within continuing hospitalization
·
Contraindication of dual antiplatelet therapy or need for anticoagulation
therapy
·
High risk of bleeding complications
·
Participation in other clinical study

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Informed consent:
All enrolled patients must give their informed consent for participation in the
study.
Endpoints:
Primary endpoint:
·
Composite of incidence of death, reinfarction, unstable angina pectoris,
stroke, unplanned rehospitalization, repeat target vessel revascularization
and stent thrombosis in 90 days after myocardial infarction
Secondary endpoint:
·
Complications associated with the puncture site requiring rreatment in 30
days after myocardial infarction
Definitions:
Myocardial infarction
Criteria for the acute myocardial infarction (MI):
evidence of myocardial necrosis in a clinical setting consistent with acute
myocardial ischaemia.
Under these conditions any one of the following criteria meets the diagnosis for
MI:
• Detection of a rise and/or fall of cardiac biomarker values [preferably cardiac
troponin (cTn)] with at least one value above the 99th percentile upper
reference limit (URL) and with at least one of the following:
-
Symptoms of ischaemia.
-
New or presumed new significant ST-segment–T wave (ST–T) changes or
new left bundle branch block (LBBB).
-
Development of pathological Q waves in the ECG.
-
Imaging evidence of new loss of viable myocardium or new regional wall
motion abnormality.
-
Identification of an intracoronary thrombus by angiography or autopsy.
• Cardiac death with symptoms suggestive of myocardial ischaemia and
presumed new ischaemic ECG changes or new LBBB,but death occurred before
cardiac biomarkers were obtained, or before cardiac biomarker values would be
increased.
• Percutaneous coronary intervention (PCI) related MI is arbitrarily defined by
elevation of cTn values (>5 x 99th percentile URL) in patients with normal

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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 (iii) angiographic findings consistent with a procedural complication
or (iv) imaging demonstration of new loss of viable myocardium or new
regional wall motion abnormality are required.
• Stent thrombosis associated with MI when detected by coronary angiography
or autopsy in the setting of myocardial ischaemia and with a rise and/or fall of
cardiac biomarker values with at least one value above the 99th percentile URL.
• Coronary artery bypass grafting (CABG) related MI 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.
Criteria for prior myocardial infarction
Any one of the following criteria meets the diagnosis for prior MI:
• Pathological Q waves with or without symptoms in the absence of non-
ischaemic causes.
• Imaging evidence of a region of loss of viable myocardium that is thinned and
fails to contract, in the absence of a non-ischaemic cause.
• Pathological findings of a prior MI.
ST-segment elevation – ECG characteristics
New ST elevation at the J point in two contiguous leads with the
cut-points: ≥0.1 mV in all leads other than leads V2–V3 where the
following cut points apply:≥0.2 mV in men ≥40 years;≥0.25 mV in men
<40 years, or ≥0.15 mV in women.
Percutaneous coronary intervention
Refers to all interventional cardiology methods for treatment coronary artery
disease
Unstable angina
is considered to be present in patients with ischemic symptoms suggestive of an
ACS and no elevation in troponin, with or without ECG changes indicative of
ischemia (eg, ST segment depression or transient elevation or new T wave
inversion).
Stroke

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Presence of focal neurological deficit, occuring due to brain vessel lesion,
persisting > 24 hours or lasting < 24 hours, if the pharmacological or non-
pharmacological treatment was applied
Target vessel revascularization
Any repeat percutaneous intervention or surgical bypass of any segment of
target vessel
Stent thrombosis:
Definite
The presence of an angiographic confirmation of stent thrombosis (the presence
of a thrombus that originates in the stent or in the segment 5 mm proximal or
distal to the stent) is associated with the presence of at least one of the following
criteria within a 48-hour window: acute onset of ischaemic symptoms at rest,
new ischaemic electrocardiographic changes that suggest acute ischaemia or
typical rise and fall in cardiac biomarkers; or in the presence of a pathological
confirmation of stent thrombosis (evidence of recent thrombus within the stent
determined at autopsy or via examination of tissue retrieved following
thrombectomy). The incidental angiographic documentation of stent occlusion
in the absence of clinical signs or symptoms is not considered a confirmed stent
thrombosis (silent occlusion).
Probable
Probable stent thrombosis is defined as the presence of any unexplained death
within the first 30 days after stent implantation, or in the presence of any MI
related to documented acute ischaemia in the territory of the implanted stent
without angiographic confirmation of stent thrombosis and in the absence of any
other obvious cause, irrespective of the time after the index procedure.
Possible
Possible stent thrombosis is defined as any unexplained death from 30 days after
intracoronary stenting until the end of follow-up.
TIMI (Thrombolysis In Myocardial Infarction) classification:
developed by TIMI study group to semiquantitatively assess coronary artery
perfusion beyond point of occlusion on coronary angiography.
TIMI 3 – complete perfusion: normal flow with complete filling of the distal
territory

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Serious adverse event
Any adverse drug experience occurring at any dose that results in any of the
following outcomes:
· Life-threatening
· Death
· Hospitalization/prolongation of hospitalization
· Congenital anomaly
· Persistent or significant disability/incapacity
· Required intervention to prevent permanent impairment/damage
Other adverse events
Adverse events that are not Serious adverse events

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Plan of study:
STEMI
Successful primary PCI
Randomization in a 1:1 ratio
(24 – 72 hours)
Standard discharge
(after 72 hours)
Early discharge
(48 – 72 hours)
Clinical control at hospital
2 - 4 days after discharge
Outpatient care accordingly
to the current local practice
Clinical or telephone control
30 (± 3) days after STEMI
Clinical or telephone control
90 (± 7) days after STEMI

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Number of probands:
Enrollment of about 150-200 patients is planned
Expected total duration of clinical investigation:
3 years
Randomization:
Patients  will  be  assigned  into  the  study  groups  by  the  method  of  simple
randomization in ratio 1:1.
The ending or interruption of study:
Whenever in the course of study the patient can end his participation in study
on basis of his decision. He will inform promptly his physician about this
decisoin.
The recruitment of the subjects will be interrupted, when the preliminary
analysis in the course ot the trial shows significant  difference in the incidence of
endpoints between the study groups.
Statistic:
All subjects, participating in the study and completing the follow-up, will be
involved into the statistical analysis. Considered rate of probands lost within
follow-up is 2%.
The adequate methods of statistical evaluation of the study results will be used.
Baseline demographic, clinical, angiographic, periprocedural data and results
will be summarized using descriptive summary statistics.
Fischer´s exact test will be used for comparison of qualitative variables between
two groups. For comparison of quantitative variables  Mann-Whitney U test,
respectively Student´s t-test will be used.  Normality of data will be assessed
with Shapiro-Wilk test. The value p < 0.05 will be considered as statistically
significant.
Open access to source data / documents:
The investigator in case of need and submission of written request gives access
to source data/documents for the purposes of clinical investigation monitoring to
ethics commitees or controlling authorities inspection.

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Data manipulation and retaining of records:
All information concerning the studied subjects will be kept in confidence to the
extent, appropriate laws and directions. Medical records and information,
obtained within clinical investigation, can be studied by doctors or medical staff
practicing the study, local healthcare authorities, auditors, ethics comitees. No
personal data of subjects participating in study will be published. Patients will
sign the informed consent with collection, transmission, processing and
archiving of personal data, including state of health in the connection with
conducted study.
Declaration of Helsinki, Ethics comitee:
Trial will be performed in agreement with Declaration of Helsinki. The approval
of local Ethics committee will be gained prior to the start of patients recruitment.
Financing:
Clinical investigation does not require special financial support.
Study registration:
Study will be registered in the international register of clinical trials
www.clinicaltrials.gov.
Publication activities:
The rseults of study will be published in reviewed medical journal and presented
on professional medical congresses.