Continuing Cardiology Education

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1 Continuing Cardiology Education REVIEW ARTICLE Risk stratification for the primary prevention of arrhythmic sudden cardiac death in post-infarction patients Part II: Cardiac magnetic resonance and electrophysiological study. Trials connecting the risk stratification approaches with the ICDs. The unexplored new eras of the stable patients with preserved ejection fraction and the patients within the early post-myocardial infarction period P. Arsenos*, S. Sideris & K. A. Gatzoulis Electrophysiology Laboratory & First Divison of Cardiology, Medical School, National and Kapodistrian, University of Athens, Athens, Greece Keywords Myocardial infarction, risk stratification, sudden cardiac death Correspondence Petros Arsenos, Athinon-Chalkidos 26, Avlonas Attikis, P.O. Box 19011, Greece. Tel/ Fax: ; Funding Information No Funding information provided. Continuing Cardiology Education, 2016; 2(3), doi: /cce2.33 Abstract Current trends on Sudden Cardiac Death (SCD) Risk Stratification complementary to the conventional markers that were presented in Part I, are Cardiac Magnetic Resonance that detects and quantifies the post-infarct tissue heterogeneity and the invasive method of Programmed Ventricular Stimulation on Electrophysiological study that reveals the vulnerable and inducible myocardial substrate. While the first generation of Risk Stratification trials examined one simple prognostic marker each time, the second generation of trials investigated in past combinations of SCD prediction markers and prognostic models reflecting different arrhythmogenesis mechanisms. The third generation of trials currently utilizes Risk Stratification strategies to indentify high-risk patients before an ICD prophylactic implantation connecting the Risk Stratification process with the ICD therapy. Intensive research on SCD is also nowadays directed to the unexplored era of patients with a Preserved Ejection Fraction and to the era of early post-myocardial infarction period. Both these subgroup patients are not protected by the current ICDs implantation guidelines because of gap in evidence. Research is going to fill in this gap. Answer questions and earn CME: /Activity.aspx Cardiac Magnetic Resonance Post-infarct fibrosis plays an important role in the arrhythmogenic myocardial architecture promoting reentrant excitation [1, 2]. Quantification of the peri-infarct zone with Myocardial Delay Enhancement during Cardiac Magnetic Resonance Imaging (CMR) in 144 patients proved a predictor of cardiovascular mortality independently from age and LVEF during a median follow up of 2.4 years [3]. Tissue heterogeneity at the infarct periphery was strongly associated with inducibility for monomorphic VT during electrophysiological or device testing [4] and the infarct gray zone as a measure of tissue heterogeneity predicted appropriate ICD activations in post-myocardial infarction patients [5, 6]. In an experimental animal model, the MRI heterogeneous zone of normal myocardial tissue mixed with post-infarct scar found to contain the critical isthmuses for ventricular tachycardia[7] while post-infarction VT-related slow conduction channels indentified by CMR in VT patients are found to correspond in location and orientation well with Endocardial Voltage Mapping indentified slow conduction channels [8]. In reverse 235 ischemic and non-ischemic patients with LVEF 35% and an ICD with small heterogeneous myocardial tissue values within the lowest tertile were at low arrhythmic risk with only a 0.7% year event rate [9]. Continuing Cardiology Education, doi: /cce2.33 (144 of 150)

2 P. Arsenos et al. Risk Stratification for Sudden Cardiac Death in Post-infarction Patients Vulnerability in Electrophysiological Testing As the myocardial infarction heals a scar remains. This fibrotic area constitutes the anatomical substrate for the initiation and maintenance of an electrical re-entry circuit that may establish a dangerous VT. Programmed ventricular stimulation evaluates the arrhythmia inducibility in the electrophysiology laboratory [10] (Figure 1). The performance of electrophysiological testing (EPT) depends on the stimulation protocol used (number and degree of prematurity of programmed extra stimuli) as well as the sites of stimulation and the underlying severity of left ventricular dysfunction, and/or the other previously mentioned non-invasive high-risk indices of an abnormal substrate and repolarization phase [10]. The value of EPT in the risk stratification process has been well documented by previous studies [11 15]. EPT was used successfully to select patients for ICD implantation in the MADIT I [16] and MUSTT [17] trials, whereas a MADIT II subanalysis reported that EPT predicted VT but not VF [18]. Following this report, the value of the method for risk stratification of the post-mi patient was partly questioned. Regardless of this, EPT is a powerful prognostic tool for the assessment of high-risk patients [19], and this has been further confirmed by recent studies [13 15]. ICDs establishment by the First Generation risk stratification studies enrolling patients based on low LVEFs and fundamental risk stratification markers Twenty years ago, it was known that the lower the LVEF, the higher the arrhythmic risk, and during that period LVEF was the main risk stratifier that could fast and efficiently discriminate the high from the low arrhythmic risk patients. For this reason, LVEF was selected as an enrollment criterion for the first trials testing the ICDs in clinical conditions. Multicenter Automatic Defibrillator Trial (MADIT I) demonstrated that ICDs reduced mortality by nearly half compared with medical therapy alone, in post- MI patients with heart failure and depressed LVEF 35% along with non-sustained VT (NSVT), and non-suppressible by procainamide sustained ventricular tachyarrhythmia on electrophysiological study (EPS) [16]. A similar in design and results study was the MUSTT which randomized post-mi patients with NSVT, LVEF 40% and inducible sustained ventricular tachyarrhythmias on EPS into an ICD versus an EP-guided conventional antiarrhythmic drug therapy approach [17]. The next study, MADIT II, randomized patients with prior MI and LVEF 30% to medical therapy or ICD implantation and announced a significant 31% reduction in the risk of death with ICD implantation [20]. A fourth one, the Sudden Cardiac Figure 1. Programmed Ventricular Stimulation in a 76-year-old post-mi patient with monomorphic sustained ventricular tachycardia induction. The patient received an ICD. APRET database NCT: Continuing Cardiology Education, doi: /cce2.33 (145 of 150)

3 Risk Stratification for Sudden Cardiac Death in Post-infarction Patients P. Arsenos et al. Death in Heart Failure Trial (SCD-HeFT), randomized 2521 ischemic and non-ischemic cardiomyopathy patients with congestive heart failure (LVEF 35%) and demonstrated a significant 23% reduction in mortality in ICD recipients compared with control patients treated with amiodarone [21]. All four studies demonstrated a significant ICD survival benefit based on a risk stratification approach of a low LVEF as far as the primary prevention of SCD. The device s benefit directly connected with the risk stratifier and in this way both the ICDs and the LVEF were incorporated into the Guidelines and a non-arrhythmic entity, the left ventricular systolic dysfunction, became the main approved arrhythmic risk stratifier for the post-mi and dilated cardiomyopathy patients selection for an ICD implantation for primary prevention of SCD during the last decade. Once again these studies demonstrated a significant ICD survival benefit based on a risk stratification approach related to a low LVEF, a policy with several limitations when considering the epidemiologic aspect of SCD. The Second Generation Studies Combining Non-invasive tests for SCD Prediction During the lasts 15 years, several studies explored the performance of combined non-invasive tests for SCD prediction (Table 1). Ikeda in 2000 combined the left ventricular systolic dysfunction (LVEF) with a depolarization abnormality marker (SAECG late potentials) and a repolarization abnormality marker (TWA) in 102 post-mi patients. The highest positive predictive value (50%) was obtained when TWA and LP were combined [22]. Exner, in 2007 in the REFINE study combined a LVEF <0.50 with the autonomic tone marker of heart rate turbulence (HRT) and the electrical substrate marker of T-wave alternans (TWA) which were assessed in two different post-mi periods (2 4 weeks versus weeks after MI). An impaired HRT with abnormal TWA, and an EF <0.50 detected by the later testing beyond 8 weeks after MI, identified patients at risk of serious events [23]. Huikuri in the CARISMA study in 2009 found that the reduced very low frequency component of heart rate variability and the induction of sustained monomorphic VT during EPS were predicting the primary endpoint of an ECG-documented ventricular fibrillation or symptomatic sustained ventricular tachycardia (VT) [14]. A New Era: SCD in Patients with Preserved Ejection Fraction Ventricular tachyarrhythmias in patients with preserved left ventricular systolic function are less common to occur in comparison to those patients with a reduced LVEF. Although the risk for SCD is lower in these patients, it is not negligible and in one post-mi cohort is estimated to be 0.6% per year [24]. Ikeda in 2006 was the first investigator trying to explore SCD prediction in preserved LVEFs by screenning post- MI patients with LVEF >40% (average 55 10%) with TWA, NSVT and SAECG Late Potentials. On multivariate analysis, a positive microvolt TWA test was the most significant predictor, with a hazard ratio of 19.7 (P < ) [24]. It is interesting that all three arrhythmia-related non-invasive indices were associated with a rather significant incidence of arrhyhtmic events. Bauer in the ISAR-Risk study in 2009 investigated HRT and DC combined. Patients found with both these autonomic function indices affected were considered suffering from severe autonomic failure (SAF). An important finding of the study was that among 2223 patients with LVEF Table 1. Studies combining non-invasive tests for SCD prediction. Study Population Tests End point Event rate Performance PPV NPV Ikeda, 2000 [22] REFINE, 2007 [23] CARISMA,2009 [14] Ikeda, 2006 [24] ISAR-R, 2009 [25] n = 102, LVEF=49% LVEF, LPs,TWA VT/VF 15% (13.8% py) n = 322,LVEF<0.50% LVEF,HRT,TWA CD/CA 11.5% (2.9% py) n = 312, LVEF=31% HRV/T,AR,LPs, VT/VF (ILR) 8% TWA,EPS (4% py) n = 1.003,LVEF>40% TWA,NSVT,LPs SCD,CA,VF 1.8% LVEF=55% (0.6% py) n = 2223, LVEF>30% HRT+DC Total Mortality 6.4% (1.3% py) HR:8.6 50% 92% HR: % 95% (VLF) HR:7 26% 95% (EPS) HR:4.8 23% 96% (TWA)HR:19.7 9% 99% HR:4.6 38% 94% LVEF, Left ventricular ejection fraction; LPs, Late Potentials; TWA, T wave alternans; HRT, heart rate turbulence; HRV, heart rate variability; AR, arrhythmias; EPS, electrophysiological study; NSVT, non-sustained ventricular tachycardia; DC, deceleration capacity of heart rate; VT, ventricular tachycardia; VF, ventricular fibrillation; CD, cardiac death; CA, cardiac arrest; ILR, implantable loop recorder; SCD, sudden cardiac death; HR, hazard ratio; VLF, very low frequencies from heart rate variability; PPV, positive predictive value; NPV, negative predictive value. Continuing Cardiology Education, doi: /cce2.33 (146 of 150)

4 P. Arsenos et al. Risk Stratification for Sudden Cardiac Death in Post-infarction Patients >30%, SAF identified another high-risk group of 117 patients with 37 deaths [25]. These trials confirmed that SCD could be predicted by different methods even among post-mi patients with preserved LVEF. The Early Post- myocardial Infarction Period Paradoxically although epidemiological data indicate an increased arrhythmic mortality early after a Myocardial Infarction, the previous two clinical trials specifically designed for investigating this issue, IRIS [26] and DYNAMIT [27], both concluded that prophylactic ICD therapy did not reduce overall mortality among high-risk patients with a recent acute myocardial infarction. As a consequence, current Guidelines based on these two trials do not recommend an early ICD implantation after myocardial infarction (classiii, Level of Evidence A) [28]. IRIS included patients with a reduced LVEF<40% and an elevated Heart rate > 90 bpm and/or NSVT while the mean LVEF was 34.6% for the ICD group. The death rates were as high as 10.6% at 1 year, a rather high event rate. DYNAMIT included post-mi patients with a depressed LVEF 35% and a depressed SDNN/HRV <70 msec or an elevated Heart rate >80 bpm. The mean LVEF in ICD group was as low as 28% while the mean SDNN was severely impaired at 61 msec, despite optimal medical therapy. The annual mortality rate in ICD group was 7.5%. Both these studies were based on LVEF and Autonomic Nervous System indices rather pointing to pump failure mortality candidates than to the arrhythmic mortality ones. Their findings were in accordance with their design, and it is clear that both these trials failed to select the arrhythmia vulnerable patients. Unfortunately the risk of SCD is highest early following MI, with a rate 6 times higher in the first month than after 1 year. The role of an electrophysiologically guided approach by performing Ventricular stimulation in all post-mi patients with a LVEF 40% before hospital discharge is promising [11 15]. This strategy is currently under prospective randomized controlled fashion investigation in the PRO- TECT-ICD study [29]. The Current status: Third Generation Studies applying Risk Stratification Strategies to Indentify High Risk Patients Most Likely to Benefit from ICD Prophylactic Implantation Research status on the field currently include trials that utilize risk stratification approaches for the selection of patients for prophylactic ICD implantation or trials that randomize patients to prove that patients identified as being at risk with the techniques used derive benefit from an ICD. Some of them are referring to post-mi patients with relatively well maintained left ventricular systolic function, a group of patients not studied in previous trials (Table 2). The efficacy of implantable defibrillator therapy after a myocardial infarction trial (REFINE-ICD/NCT ) It consists of the next step of the previous REFINE trial. It recruits post-mi patients with LVEF since The patients with abnormal HRT and abnormal TWA measured in Holter recordings were randomized to ICD or to Conventional therapy group [30]. Results are expected. Table 2. Current studies applying a Risk Stratification-guided ICD prophylactic therapy. Study Population Tests Randomization/ Intervention End point Status Reference REFINE-ICD ( ) CMR GUIDE ( ) PRESERVE EF ( ) PROTECT ICD ( ) n = 1400 LVEF: 36 50% n = 428 LVEF: 36 50% n = 1000 LVEF>40% n = 1058 LVEF 40% HRT/TWA ICD vs Control TM Recruiting NCT [30] LGE on CMR ICD vs ILR SCD and VT Recruiting NCT [31] NIRS+EPS No randomization SCD,VT,ICD Recruiting NCT ICD after EPS activation [32, 33] EPS 2-40 days Post-MI ICD vs Control CA,VT,VF,SCD Recruiting ACTRN [29] LVEF, left ventricular ejection fraction; HRT, heart rate turbulence; TWA, T wave alternans; LGE, late gadolinium enhancement; CMR, cardiac magnetic resonance; NIRS, non-invasive risk stratification; EPS, electrophysiological study; ICD, implantable cardiac defibrillator; ILR, implantable loop recorder; TM, total mortality; SCD, sudden cardiac death; VT, ventricular tachycardia; CA, cardiac arrest; VF, ventricular fibrillation. Continuing Cardiology Education, doi: /cce2.33 (147 of 150)

5 Risk Stratification for Sudden Cardiac Death in Post-infarction Patients P. Arsenos et al. The cardiac magnetic resonance-guided management of mild to moderate left ventricular systolic dysfunction trial. (CMR GUIDE/NCT ) A multicentre randomized controlled trial in which 428 patients with mild to moderate left ventricular systolic dysfunction (either ICM or NICM) and ventricular scar/ fibrosis on cardiovascular magnetic resonance are randomized to either ICD or implantable loop recorder (ILR) insertion and are followed up for 3 years. The primary hypothesis is that among patients with mild to moderate left ventricular systolic dysfunction, a routine CMR-guided management strategy of ICD insertion is superior to a conservative strategy of standard care [31]. The Risk Stratification in Patients With Preserved Ejection Fraction trial (PRESERVE EF/NCT ) This observational and interventional study is currently selecting asymptomatic post-mi patients late after MI (40 days after STEMI and N-STEMI) with preserved ejection fraction (LVEF 40%) and absence of active ischemia evaluating their arrhythmic risk based on a combined two steps non-invasive and Invasive approach. The first step is based on multiple Non-invasive markers evaluation. Patients found at risk are subsequently undergoing programmed ventricular stimulation. Inducible patients receive an ICD with the hypothesis of an appropriate device activation during follow up and improved survival [32, 33]. The Programmed ventricular stimulation to risk stratify for early cardioverterdefibrillator (ICD) implantation to prevent tachyarrhythmias following acute myocardial infarction trial. (PROTECT-ICD/ ACTRN ) Focusing on the early (2 40 days) post-mi period, this study selects the patients with a depressed LVEF 40% for an electrophysiologically study-guided early prophylactic ICD implantation (first 40 days) for primary prevention of SCD [29]. Future Trends on Risk Stratification Innovative research is evolving in the field of complex cardiac, respiratory and brain bio-signals. Open signal databases and downloadable programs facilitate international interdisciplinary research. Such important e-sites and groups include: (1) Physionet with the MIT-BIH Arrhythmia Database ( (2) The Working Group of Biological SignalAnalyses of TUM ( (3) The AcademicWorking Group of Eberhard-Karls-Universit at T ubingen ( (4) The Working Group on in e-cardiology of the European Society of Cardiology ( (5) The International Scientific Conference, Computing in Cardiology ( (6) The International Society of Holter and Non-invasive Electrocardiology ( Relevant to the daily clinical practice, the evolution of technology made possible all the noninvasive markers to be incorporated into the Holter software. Risk stratification has been simplified. Collection and analysis of massive prognostic information from just a simple daily heart signal recording during hospitalization, or in out-patient clinics or even in the private cardiology office consist already a daily routine. Innovative technology and research on Holter enforced doctors, providing them with the tools for protecting their patients. This first non-invasive screening is possible to be completed by a cardiologist even in a private external cardiology office and the patients found under risk to be referred for EPS and/or CMR further evaluation. Conflict of Interest All authors have nothing to disclose. References 1. Peters, NS, and AL Wit Myocardial architecture and ventricular arrhythmogenesis. Circulation 97: Bakker, JM, F Capelle, MJ Janse et al Reentry as a cause of ventricular tachycardia in patients with chronic ischemic heart disease:electrophysiologic and anatomic correlation. Circulation 77: Yan, TA, AJ Shayne, KA Brown et al Characterization of the peri-infarct zone by contrastenhanced cardiac magnetic resonance imaging is a powerfull predictor of post- myocardial infarction mortality. Circulation 114: Schmidt, A, CF Azevedo, A Cheng et al Infarct tissue heterogeneity by magnetic resonance imaging identifies enhanced cardiac arrhythmia susceptibility in patients with left ventricular dysfunction. Circulation 115: Roes, SD, JW Borleffs, RJ van der Geest et al Infarct tissue heterogeneity assessed with contrast-enhanced mri predicts spontaneous ventricular arrhythmia in patients with ischemic cardiomyopathy and implantable cardiovberter-defibrillator. Circ. Cardiovasc. Imaging 2: Continuing Cardiology Education, doi: /cce2.33 (148 of 150)

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7 Risk Stratification for Sudden Cardiac Death in Post-infarction Patients P. Arsenos et al. Infarction (REFINE-ICD). Available at www. clinicaltrials.gov. 31. ClinicalTrials.gov Identifier: NCT Cardiac Magnetic Resonance GUIDEd Management of Mild to moderate Left Ventricular Systolic Dysfunction trial. (CMR GUIDE). Available at www. clinicaltrials.gov. 32. ClinicalTrials.gov Identifier: NCT The Risk Stratification in Patients With Preserved Ejection Fraction trial (PRESERVE EF) Available at www. clinicaltrials.gov. 33. Gatzoulis, KA, D Tsiachris, P Arsenos et al Post myocardial infarction risk stratification for sudden cardiac death in patients with preserved ejection fraction: PRESERVE-EF Study design. Hellenic J. Cardiol. 55: Continuing Cardiology Education, doi: /cce2.33 (150 of 150)