1. Date of download: 6/25/2016 Copyright © The American College of Cardiology. All rights reserved. From: Indications for Implantable Cardioverter-Defibrillators Based on Evidence and Judgment J Am Coll Cardiol. 2009;54(9):747-763. doi:10.1016/j.jacc.2009.03.078 Timeline of Evolution of ICDs From Original Concept to Present The concept of an implantable cardioverter-defibrillator (ICD) originated in the late 1960s, and the development of the technology and proof of concept leading to the first clinical implant extended to 1980. From 1980 until late 1996, data supporting ICD benefit were largely observational, or based on small high-risk cohorts or case-control studies. The first true randomized trials were designed in the late 1980s and early 1990s, and all of the major trials for both primary and secondary indications were published during an interval of <10 years between late 1996 and early 2005. Additional studies since then have aided in the interpretation of the outcomes from the clinical trials, but there remains a need for consolidation and clarification and for additional data to better define efficiency of therapy and targeted selection of individual candidates who have a high likelihood of benefit. AVID = Antiarrhythmic Versus Implantable Defibrillator; CABG-Patch = Coronary Artery Bypass Graft-Patch; CASH = Cardiac Arrest Study of Hamburg; CAST = Cardiac Arrhythmia Suppression Trial; CIDS = Canadian Implantable Defibrillator Study; DEFINITE = Defibrillators In Non- Ischemic Cardiomyopathy Treatment Evaluation; DINAMIT = Defibrillator In Acute Myocardial Infarction Trial; FDA = Food and Drug Administration; MADIT = Multicenter Automatic Defibrillator Implantation Trial; MUSTT = Multicenter Unsustained Tachycardia Trial; SCD-HeFT = Sudden Cardiac Death-Heart Failure Trial. Figure Legend:

2. Date of download: 6/25/2016 Copyright © The American College of Cardiology. All rights reserved. From: Indications for Implantable Cardioverter-Defibrillators Based on Evidence and Judgment J Am Coll Cardiol. 2009;54(9):747-763. doi:10.1016/j.jacc.2009.03.078 Variable Phenotypic Expression in Gene-Positive LQT Syndrome Patients Variable expression confounds the interpretation of the genetics of the inherited long-QT (LQT) syndrome and can be viewed as a multistage expression algorithm. Expression level I in gene-positive subjects refers to whether and to what extent the corrected QT interval lengthens predictably based on the presence of a genetic variant plus environmental influences. At expression level II, referring to phenotypic expression of clinical events, such as syncope, arrhythmias, cardiac arrest, and sudden cardiac death, variability occurs with both physiological and environmental modifiers. This feature of long-QT syndrome influences the difficulty in the decision-making process for implantable cardioverter-defibrillators in gene-positive carriers of related probands, with and without baseline expression of corrected QT prolongation. No quantitative distribution of the various patterns of electrocardiographic (ECG) phenotype/arrhythmia phenotype is intended because of lack of sufficient data. However, ECG(−)/arrhythmia(+) is likely far less common than ECG(+)/arrhythmia(−). Modified, with permission, from Myerburg and Castellanos (56). Figure Legend:

3. Date of download: 6/25/2016 Copyright © The American College of Cardiology. All rights reserved. From: Indications for Implantable Cardioverter-Defibrillators Based on Evidence and Judgment J Am Coll Cardiol. 2009;54(9):747-763. doi:10.1016/j.jacc.2009.03.078 Entry Criteria for EF and EFs of Subjects Enrolled in ICD Trials Each of these 4 primary prevention trials had a qualifying ejection fraction (EF) cutoff (green circles), above which patients were not enrolled (grey bars). In each study, the EF subgroup that dominated enrollment (solid blue bars) (mean ± SD for MADIT and MADIT II and median and interquartile ranges for MUSTT and SCD-HeFT) received a measurable benefit from implantable cardioverter- defibrillator (ICD) therapy, whereas those with EFs closer to the threshold entry criterion (cross-hatched blue bars) achieved no benefit or an uncertain benefit (see text on ejection fraction data). Used with permission, from Myerburg (63). AM = ambulatory monitor; EPS = electrophysiological study; HF = heart failure; other abbreviations as in Figure 1. Figure Legend:

4. Date of download: 6/25/2016 Copyright © The American College of Cardiology. All rights reserved. From: Indications for Implantable Cardioverter-Defibrillators Based on Evidence and Judgment J Am Coll Cardiol. 2009;54(9):747-763. doi:10.1016/j.jacc.2009.03.078 Estimates of Incidence and Total Annual Population Burden for General Adult Population and Increasingly High-Risk Subgroups The overall adult population has an estimated sudden death incidence of 0.1% to 0.2% per year, accounting for a total of >300,000 events per year. With the identification of increasingly powerful risk factors, the incidence increases progressively, but it is accomplished by a progressive decrease in the total number of events represented by each group. The inverse relationship between incidence and total number of events occurs because of the progressively smaller denominator pool in the highest subgroup categories. The blue-hatched incidence bars for the higher risk groups represent estimates from the original analysis in the 1990s; the superimposed red-hatched bars reflect more recent estimates based on the effects of newer multimodal therapies. Successful interventions among larger population subgroups require identification of specific markers to increase the ability to identify specific patients who are at particularly high risk for a future event. (Note: The horizontal axis for the incidence figures is not linear.) Modified, with permission, from Myerburg et al. (86). CAD = coronary artery disease; EF = ejection fraction. Figure Legend:

5. Date of download: 6/25/2016 Copyright © The American College of Cardiology. All rights reserved. From: Indications for Implantable Cardioverter-Defibrillators Based on Evidence and Judgment J Am Coll Cardiol. 2009;54(9):747-763. doi:10.1016/j.jacc.2009.03.078 Distribution of Clinical Status of Victims at Time of SCD Nearly two-thirds of cardiac arrests occur as the first clinically manifest event or in the clinical setting of known disease in the absence of strong risk predictors. Less than 25% of the victims have high-risk markers based on arrhythmic or hemodynamic parameters. Modified, with permission, from Epstein (87). AP = angina pectoris; MI = myocardial infarction; SCD = sudden cardiac death. Figure Legend:

6. Date of download: 6/25/2016 Copyright © The American College of Cardiology. All rights reserved. From: Indications for Implantable Cardioverter-Defibrillators Based on Evidence and Judgment J Am Coll Cardiol. 2009;54(9):747-763. doi:10.1016/j.jacc.2009.03.078 Comparison of Appropriate ICD Discharge Rate and Survival Benefit From MADIT II The survival curve demonstrates the probability of appropriate implantable cardioverter-defibrillator (ICD) therapy at 1, 2, and 3 years of follow-up. The insert demonstrates the excess mortality among control patients without ICDs at the same 3 points in time. These figures demonstrate that appropriate ICD discharges cannot be considered a surrogate for survival, and do not accurately indicate the magnitude of benefit expected from ICD recipients. VT/VF = ventricular tachycardia/fibrillation. Modified, with permission, from Moss AJ et al. (110). Figure Legend: