Post Myocardial Infarction Risk Stratification for Sudden Cardiac Death in Patients With Preserved Ejection Fraction: PRESERVE-EF
Conditions: Myocardial Infarction
Sponsor: University of Athens

1 
 
Post Myocardial Infarction Risk Stratification for Sudden Cardiac Death in Patients 
with Preserved Ejection Fraction (PRESERVE EF) Study 
Clinicaltrials.gov identifier: NCT02124018 
January 23rd 2019 
 
 

2 
 
Methods  
Trial oversight: The PRESERVE EF study is a multicenter, prospective, observational cohort study 
(clinicaltrials.gov identifier NCT02124018) with seven Cardiology departments in Greece actively 
participating. Study protocol was approved by all institutions’ ethics committees and was endorsed by the 
Hellenic Society of Cardiology with an anonymized online database created and maintained in its servers(1).  
Patients: Post-angiographically proven MI patients, at least 40 days after the event (90 days after surgery if 
they underwent coronary artery bypass grafting)(2, 3), with LVEF≥40% (also assessed after 40 or 90 days, 
respectively from the index event), either revascularized or not – but without any evidence of active ischemia 
(following negative myocardial scintigraphy/exercise treadmill test/stress echocardiography in the previous 6 
months), on optimal tolerated medical therapy, were enrolled. Exclusion criteria were: (1) Presence of a 
secondary prevention indication for ICD implantation, (2) Presence of a permanent pacemaker, due to 
potential effects on NIRF acquisition following pacemaker dependency and cardiac memory(4),  (3) 
Persistent, long-standing persistent and permanent atrial fibrillation, (4) Neurological symptoms (presyncope 
or syncope) within the last 6 months, (5) Patients with systemic illnesses (cancer, liver failure, end-stage renal 
disease, rheumatic diseases and thyroid dysfunction), (6) Administration of antiarrhythmic medication other 
than β-blockers, (7) Age ≥80 or ≤18 years old. 
All patients provided written informed consent.  
Study protocol: A two-step stratification algorithm was implemented(1). Upon the first step of the algorithm, 
an ambulatory 24-hour, as well as signal-averaged electrocardiogram recordings were obtained and evaluated 
for the presence of the following NIRFs(1, 5-8): (1) >30 premature ventricular complexes/hour on 24-hour 
electrocardiography, (2) presence of non-sustained ventricular tachycardia on 24-hour electrocardiography, 
(3) 2/3 positive criteria for late potentials, either conventional or modified(8), (4) QTc derived from 24-hour 
electrocardiography >440ms (men) or >450ms (women)(6) according to the Fridericia formula from a signal 
recorded in 3 pseudo-orthogonal leads, (5) Ambulatory T-wave alternans ≥65μV in two Holter channels(5), 
(6) Standard deviation of normal RR intervals ≤75ms on the 24-hour electrocardiography, (7) Deceleration 
capacity ≤4.5ms and heart rate turbulence onset ≥0% and heart rate turbulence slope ≤2.5ms(7). 

3 
 
In the presence of at least one NIRF, patients underwent invasive PVS and were classified as inducible if 
sustained monomorphic ventricular tachycardia or ventricular flutter or polymorphic ventricular tachycardia 
were induced. The arrhythmia induced was defined as sustained monomorphic ventricular tachycardia when 
a uniform morphology of QRS complexes with a rate between 120-220bpm was observed, while persisting 
for ≥30 seconds (or shorter, if termination was necessary due to hemodynamic instability). Faster rates of 
regular monomorphic ventricular tachycardia (≥220bpm) not permitting QRS complexes to be readily 
distinguished from T waves and without deterioration towards fibrillation, were defined as ventricular flutter, 
but they were included in the monomorphic category. Polymorphic ventricular tachycardia was defined if 
constantly changing morphologies and axis were present, eventually degenerating into fibrillation. See 
“Appendix” for PVS protocol details. 
Patients with paroxysmal atrial fibrillation were evaluated for NIRF presence and submitted to PVS while on 
sinus, with same stimulation protocol implemented in all cases. 
Risk level groups: After completion of the study protocol, patients were stratified into three groups: 
• Group 1 –No NIRFs present – no invasive PVS performed 
• Group 2 – At least one NIRF present – noninducible upon PVS 
• Group 3 – At least one NIRF present AND inducible upon PVS. 
An ICD was offered only to Group 3 patients. 
Patients declining PVS were considered not to have completed stratification and were not included in the 
protocol performance and survival analyses, yet were followed up as scheduled for the occurrence of any 
events. Patients completing the protocol but declining an offered ICD were fully included in all analyses.  
ICD programming: In accordance with trials favouring prolonged detection intervals at higher rates for the 
avoidance of treatment of self-terminating arrhythmic events(9), ventricular tachycardia therapy cycle length 
was set to 330msec and number of intervals to detect to 32. Fibrillation therapy cycle length was set to 
270msec and number of intervals to detect to 18/24. In devices with time programming, the same cycle lengths 
were used but intervals were set to 7sec for CLs in the 270-330msec range and to 2.5sec for CLs<270msec. 

4 
 
Ventricular tachycardia therapy consisted of several attempts of antitachycardia pacing, followed by 
cardioversion at progressively increasing energy. High-energy shocks were administered to terminate 
ventricular fibrillation. In 32 cases dual-chamber ICDs were inserted, while in the remaining 5 a single-
chamber device was chosen by both the primary and implanting physicians, after excluding the presence of 
bradyarrhythmic aberration on the electrophysiological study. 
Follow up: Implanted patients were followed up every three months, and nonimplanted patients every six 
months. Events included cardiac (sudden and nonsudden) and non-cardiac death. Acute coronary syndromes 
and/or repeat revascularization events were also recorded. All device activation were adjudicated 
independently by two electrophysiologists (D.T. and P.A.). In case of discrepancy, a third electrophysiologist 
(K.A.G.) reviewed the event. 
Outcomes: The primary endpoint of the study was the occurrence of MAEs, namely either SCD/clinical 
ventricular tachycardia/fibrillation or/and appropriate ICD activation. SCD was defined as death occurring 
within one hour of symptom onset if no evidence of alternative causes was present. Death was considered 
nonsudden cardiac if occurring in the context of heart failure deterioration. All other deaths were classified as 
noncardiac. The secondary endpoint was total mortality. 
Statistics: The primary goal of the study was to assess the proposed two-step PVS-inclusive risk stratification 
algorithm’s ability to identify a subpopulation of post-myocardial infarction patients with left ventricular 
ejection fraction≥40% at risk for MAEs. To that end, the study was designed to have a statistical power of 
80% for detecting free from primary endpoint occurrence survival curve divergence at the 0.05 significance 
level(1). All continuous variables were checked for normality of distribution, using the Shapiro-Wilk test. 
Regarding those with normal distribution, Student’s t-test was used for all comparisons. In case of non-
normality, the Mann-Whitney U-test was used. In cases of categorical variables Fisher’s exact test was used. 
Binary logistic regression was used to compare the odds ratio between groups with different number of NIRFs 
regarding inducibility. Kaplan-Meier curves were used to visualize survival free from primary endpoint 
occurrence and the logrank test was applied to assess the presence of statistically significant differences. A 
two-sided p-value of ≤0.05 was considered statistically significant in all cases.  

5 
 
Power analysis(1): Due to the paucity of data regarding PVS yield in similar population cohorts, it was 
necessary to use metrics derived from noninvasive indices included in this Study as well. After setting the 
type I error probability for a two sided test at 5% and the power of our study at 80%, SDNN was found to be 
the variable that required the largest sample (a ratio of high SDNN patients/controls to low SDNN 
patients/exposed equal to 12 was anticipated). The anticipated accrual/mean follow up intervals were 2 and 3 
years, respectively. Relative risk (based on SDNN performance) of control subjects relative to exposed 
subjects was equal to 0.65. Based on the above, 66 exposed subjects and 792 control subjects would need to 
be studied to be able to reject with a probability of 80% the null hypothesis that the exposed and control 
survival curves are equal. 
1. 
Gatzoulis KA, Tsiachris D, Arsenos P, Dilaveris P, Sideris S, Simantirakis E, et al. Post myocardial infarction risk 
stratification for sudden cardiac death in patients with preserved ejection fraction: PRESERVE-EF study design. Hellenic 
journal of cardiology : HJC = Hellenike kardiologike epitheorese. 2014;55(5):361-8. 
2. 
Hohnloser SH, Kuck KH, Dorian P, Roberts RS, Hampton JR, Hatala R, et al. Prophylactic use of an implantable 
cardioverter-defibrillator after acute myocardial infarction. The New England journal of medicine. 2004;351(24):2481-
8. 
3. 
Steinbeck G, Andresen D, Seidl K, Brachmann J, Hoffmann E, Wojciechowski D, et al. Defibrillator implantation 
early after myocardial infarction. The New England journal of medicine. 2009;361(15):1427-36. 
4. 
Shvilkin A, Huang HD, Josephson ME. Cardiac memory: diagnostic tool in the making. Circulation Arrhythmia 
and electrophysiology. 2015;8(2):475-82. 
5. 
Verrier RL, Klingenheben T, Malik M, El-Sherif N, Exner DV, Hohnloser SH, et al. Microvolt T-wave alternans 
physiological basis, methods of measurement, and clinical utility--consensus guideline by International Society for 
Holter and Noninvasive Electrocardiology. Journal of the American College of Cardiology. 2011;58(13):1309-24. 
6. 
Arsenos P, Gatzoulis KA, Dilaveris P, Gialernios T, Sideris S, Lazaros G, et al. The rate-corrected QT interval 
calculated from 24-hour Holter recordings may serve as a significant arrhythmia risk stratifier in heart failure patients. 
International journal of cardiology. 2011;147(2):321-3. 
7. 
Bauer A, Barthel P, Schneider R, Ulm K, Muller A, Joeinig A, et al. Improved Stratification of Autonomic 
Regulation for risk prediction in post-infarction patients with preserved left ventricular function (ISAR-Risk). European 
heart journal. 2009;30(5):576-83. 
8. 
Gatzoulis KA, Carlson MD, Biblo LA, Rizos I, Gialafos J, Toutouzas P, et al. Time domain analysis of the signal 
averaged electrocardiogram in patients with a conduction defect or a bundle branch block. European heart journal. 
1995;16(12):1912-9. 
9. 
Gasparini M, Proclemer A, Klersy C, Kloppe A, Lunati M, Ferrer JB, et al. Effect of long-detection interval vs 
standard-detection interval for implantable cardioverter-defibrillators on antitachycardia pacing and shock delivery: 
the ADVANCE III randomized clinical trial. Jama. 2013;309(18):1903-11.