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Available online at www.sciencedirect.com
www.elsevier.com/locate/tcm
The implantable cardioverter–defibrillator: An update Jared D. Miller, Omair Yousuf, and Ronald D. Bergern Department of Medicine, Johns Hopkins University, Baltimore, MD
abstra ct The implantable cardioverter–defibrillator (ICD) provides life-saving therapy to prevent sudden cardiac death. ICDs have been implanted in millions of patients worldwide since the first human implant in 1980. Clinical trials have helped establish guidelines for ICD implantation in primary and secondary prevention of sudden cardiac death. Recent trials have also tested and compared various programing strategies to avoid unnecessary shocks and improve survival among ICD recipients. ICDs may also assist with monitoring for heart failure management. In this review, we discuss the clinical science to date that has helped define the role of ICDs in current practice. & 2015 Elsevier Inc. All rights reserved.
Brief history of the ICD The implantable cardioverter–defibrillator (ICD) has emerged as an important tool for the prevention of sudden cardiac death (SCD) in selected patients. SCD frequently occurs from sustained rapid ventricular tachycardia (VT) or VT that degenerates into ventricular fibrillation (VF). Claude Beck is credited with saving the first human life with defibrillation of VF in an operating room in 1947 [1]. While management of ventricular arrhythmias in the hospitalized setting improved with the advent of coronary care units in the 1960s, the majority of SCD events occur outside medical facilities and resuscitative efforts for out-of-hospital cardiac arrest are abysmal, with only an estimated 8% of patients surviving to hospital discharge [2]. These early accomplishments, coupled with the enormous challenge of preventing sudden death in the outpatient setting, paved the road for the landmark work and contributions by Dr. Michel Mirowski and colleagues. Despite significant skepticism in the medical community during their initial efforts, the first human implantation of an ICD was performed in 1980 at Johns Hopkins Hospital [3].
Over the last three decades, significant progress has been made in ICD design and programing to maximize therapeutic benefit and minimize patient discomfort. Today, ICD therapy is the standard of care in the primary and secondary prevention of sudden cardiac death.
Clinical science/trials Current guidelines support the use of ICD therapy for primary and secondary prevention of SCD in specific clinical situations [4]. In the context of ICD therapy, primary prevention is defined as interventions performed to prevent SCD, whereas secondary prevention refers to therapies aimed at preventing SCD in those who have already experienced life-threatening VT/VF. These guidelines are well informed by large randomized clinical trials demonstrating the efficacy of ICD therapy. This review will summarize the landmark primary and secondary prevention trials and their implications in current practice.
Dr. Berger is a consultant for Boston Scientific Corp. The other authors have indicated there are no conflicts of interest. n Correspondence to: Ronald D. Berger, MD, PhD, Johns Hopkins Hospital, Halsted 570, 600 N Wolfe St, Baltimore, MD 21287. Tel.: þ1 410 614 2751; fax: þ1 410 502 4854. E-mail address: [email protected] (R.D. Berger). http://dx.doi.org/10.1016/j.tcm.2015.01.015 1050-1738/& 2015 Elsevier Inc. All rights reserved.
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Secondary prevention Patients with prior cardiac arrest are at significantly higher risk of recurrent arrest and SCD. With the exception of amiodarone, anti-arrhythmic drugs have failed to improve survival or reduce the frequency of ventricular arrhythmias. The first landmark study, Anti-arrhythmics Versus Implantable Defibrillators (AVID) study, enrolled patients with prior resuscitation for VF or cardioversion for sustained ventricular tachycardia (VT) and randomized them to ICD therapy or Class III anti-arrhythmics (primarily amiodarone) [5]. There was a significant reduction in the primary endpoint of mortality in the ICD group at three-year follow-up. Subgroup analyses demonstrated the greatest benefit in those with significantly reduced left ventricular (LV) systolic function. The Canadian Implantable Defibrillator Study (CIDS) randomized patients with resuscitated VT or VF or unmonitored syncope to an ICD versus amiodarone [6]. A nonsignificant but consistent reduction in all-cause and arrhythmic mortality was observed with ICD therapy. Similar to CIDS, the Cardiac Arrest Study Hamburg (CASH) observed a nonsignificant reduction in mortality in ICD therapy compared to amiodarone/metoprolol therapy in patients with a history of cardiac arrest from ventricular arrhythmia [7]. Metaanalyses of these three studies demonstrated significant reduction in all-cause and arrhythmic mortality with ICD therapy [8]. The summation of these studies has led to current practice guidelines in which ICD therapy is indicated for survivors of cardiac arrest due to VF or hemodynamically unstable sustained VT, irrespective of LV function, following an evaluation to define the cause of the arrhythmia and exclusion of reversible causes. Notably, in the AVID registry, patients with a transient or correctable cause of VT/VF, including recent myocardial infarction, acute ischemia, drug overdose, or severe electrolyte imbalance who did not receive an ICD surprisingly had high subsequent mortality [9]. Thus, ICD therapy may be appropriate even in selected cases when the underlying cause of the arrhythmia is thought to be correctable.
Primary prevention Survivors of out-of-hospital cardiac arrest represent a very small fraction of those who may benefit from an ICD. There is a strong desire to identify patients at highest risk and treat them prophylactically with ICD therapy. A number of studies have helped establish the role of a primary prevention ICD in both ischemic and non-ischemic cardiomyopathy. The Multicenter Unsustained Tachycardia Trial (MUSTT) randomized patients with prior MI, left ventricular ejection fraction (LVEF) r40%, documented non-sustained VT (NSVT), and inducible VT to electrophysiology (EP) study-guided management versus standard medical care [10]. This study demonstrated survival benefit only in patients within the EP study-guided therapy arm who received an ICD, whereas those receiving anti-arrhythmic drugs did not show similar benefit. Similarly, the Multicenter Automatic Defibrillator Implantation Trial (MADIT) randomized patients with prior MI, LVEF r35%, documented NSVT, and inducible VT at EP study, which was not suppressible with procainamide, to ICD versus
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medical therapy (primarily amiodarone) [11]. There was a relative 54% all-cause mortality reduction in the ICD group. The follow-up MADIT II study was performed to evaluate the role of an ICD in a broader population without the need for ambient or inducible arrhythmia at EP study prior to enrollment [12]. This landmark study randomized 1232 patients with a prior MI and LVEF r30% to an ICD versus conventional medical therapy. ICD therapy was associated with a 49% relative reduction in all-cause mortality. To date, the largest study of ICD therapy in primary prevention heart failure patients was the Sudden Cardiac Death in Heart Failure study (SCD-HeFT), which randomized 2521 patients with NYHA Class II or III heart failure and LVEF r35% with ischemic or non-ischemic substrate, to ICD, amiodarone, or placebo [13]. There was no difference in mortality between the amiodarone and placebo groups, but there was a 23% relative reduction in mortality in the ICD arm with an absolute risk reduction of 7.2%. The benefit of ICD therapy was similar in ischemic and non-ischemic substrates, and greater benefit was seen in those with NYHA Class II symptoms as opposed to those with NYHA Class III heart failure. The Cardiomyopathy Trial (CAT), Amiodarone versus Implantable Defibrillator (AMIOVIRT), and Defibrillators in Non-Ischemic Cardiomyopathy Treatment Evaluation (DEFINITE) studies were limited to patients with non-ischemic cardiomyopathies [14–16]. While several of these small studies failed to show any survival benefit with ICD therapy, the DEFINITE study, which included patients with non-ischemic dilated cardiomyopathy, LVEF o 36%, and premature ventricular contractions or NSVT, demonstrated a trend toward reduction in total mortality and a significant reduction in arrhythmic death with ICD therapy. A meta-analysis confirmed a significant reduction in mortality with ICD therapy in patients with non-ischemic cardiomyopathy [17]. The findings of these studies, in combination with the results of SCD-HeFT, have established the role of ICD therapy in this population. While most studies to date have expanded the role of ICD therapy in clinical practice, ICD therapy in selected populations has demonstrated a lack of efficacy. In the Coronary Artery Bypass Graft (CABG) Patch trial, patients with a LVEF r35% and abnormalities on signal-averaged electrocardiogram, who underwent revascularization with elective coronary bypass surgery, were randomized to ICD therapy or conventional therapy [18]. There was no difference in overall mortality between the two groups. Similarly, the Defibrillator in Acute Myocardial Infarction (DINAMIT) trial randomized patients with LV dysfunction and impaired cardiac autonomic function, who were 6–40 days post-MI, to ICD versus no ICD therapy showed no difference in overall mortality [19]. ICD implantation after MI was also evaluated by the Immediate Risk Stratification Improves Survival (IRIS) study, in which patients within 5–31 days after a MI with LVEF r 40%, heart rate greater than 90 beats per minute (BPM) or nonsustained VT on Holter monitoring were randomized to ICD or standard medical therapy [20]. ICD therapy conferred no additional benefit in mortality reduction. The totality of these studies has solidified recommendations for ICDs not to be implanted in the peri-MI or peri-revascularization period.
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ICDs in other high-risk populations The majority of studies in ICD therapy have been focused on those with structural heart disease and reduced LVEF, which constitute the largest group of patients at risk. However, numerous other conditions are known to be associated with an increased risk of sudden cardiac death. Though these populations are too small for large randomized trials, observational analyses have helped define cohorts that may benefit from ICDs. One such high-risk group includes those with inherited abnormalities of ion channels, including longQT syndrome, Brugada syndrome, and catecholaminergic polymorphic VT. Another such group includes those with structural heart disease such as hypertrophic cardiomyopathy (HCM) or arrhythmogenic right ventricular dysplasia/ cardiomyopathy (ARVD/C) [21]. The risk factors of SCD in HCM populations have been well studied in observational trials. ICD therapy is indicated in those with HCM and at least one of the following major risk factors: SCD in a first-degree relative, maximal LV wall thickness Z30 mm, and unexplained syncope [22]. There is a clear role for ICD therapy for secondary prevention in ARVD/C and other inherited high-risk conditions. While the predictive markers for SCD in ARVD/C are still being elucidated [23–25], a primary prevention ICD is recommended for those with ARVD/C who have at least one additional risk factor [4].
Current guidelines Consensus guideline statements have largely followed the results of the clinical trials discussed above. The 2008 ACC/ AHA/HRS guideline statement, which was updated in 2012, has been an important clinical guide both for physicians and for informing reimbursement for ICD expenses [4,26]. As per the results of AVID, CIDS, and CASH, ICDs are a Class I indication in secondary prevention for survivors of VF or hemodynamically unstable VT without a readily reversible cause. Additional Class I indications in secondary prevention include those with structural heart disease and sustained VT, or syncope of unknown origin and VT or VF induced at EP study. In primary prevention, an ICD is indicated in those with LVEF r 35%, NYHA Class II or III heart failure, and those who are at least 40 days post-MI. This guideline is consistent with the inclusion criteria of SCD-HeFT and is inclusive of the findings of DINAMIT and IRIS in post-MI patients. While most patients require a LVEF of r35% to be eligible for primary prevention ICD therapy, post-MI patients with NYHA Class I heart failure may have a LVEF of 30%—a recommendation based on the inclusion criteria of the MADIT II study. The final Class I indication for ICD implantation arises from the results of MUSTT, which included patients with prior MI and LVEF r 40%, non-sustained VT who have inducible VT, or sustained VF during an EP study. A number of Class IIa indications exist for commonly encountered situations in which the evidence is not as robust. ICD therapy is reasonable in those with unexplained syncope, LV dysfunction, and non-ischemic dilated cardiomyopathy (DCM) or those with sustained VT and near-normal LV
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function. Class IIa indications also include inherited abnormalities of ion channels and structural heart disease such as HCM or ARVD/C. ICD therapy is not recommended in certain populations (Class III indications), including those with life expectancy less than one year, NYHA Class IV heart failure, significant psychiatric illness that would be exacerbated by device implantation or prevent routine follow-up, VF or VT due to a reversible disorder, or ventricular arrhythmias that are amenable to surgical or catheter ablation. Despite the existence of numerous clinical trials in ICD therapy, many nuanced clinical situations exist, which have not been evaluated in randomized trials and are therefore not discussed in current guidelines. This has become especially important with regards to reimbursement of ICD implantation. A recently published expert consensus document outlines various clinical scenarios outside of guideline-directed recommendations [27]. These include device therapy recommendations for patients within 40 days of a MI or within 90 days of revascularization who have an alternate indication for device therapy, such as pacing for bradyarrhythmia. Because scenarios such are these and many others will likely never be evaluated in large-scale clinical trials, such expert consensus statements are important in helping to define appropriate ICD use.
ICD Programing In addition to critical progress in identifying patient populations who benefit from ICD therapy, important clinical studies have also provided guidance in optimization of ICD programing. A number of randomized trials have tested different tachycardia detection strategies and the use of available therapies to help optimize ICD benefit while minimizing side effects, most notably unnecessary shocks. Both appropriate and inappropriate ICD shocks have been strongly associated with psychological effects and reduced quality of life [21]. The efficacy of anti-tachycardia pacing (ATP) to terminate VT has been established in clinical trials. The Pacing Fast Ventricular Tachycardia Reduces Shock Therapies (Pain-FREE Rx II) trial demonstrated the safety and effectiveness of ATP in fast VT [28]. Patients were randomized to ICD programing with either traditional shock therapy for rates 4200 bpm versus ATP followed by a shock if ineffective. There was no difference between groups in episode duration, syncope, or sudden cardiac death. The ATP arm had fewer shocks delivered and ATP therapy was successful in terminating 72% of VT episodes. Regarding arrhythmia detection, ICDs were initially programed to detect tachycardia on the basis of heart rate alone. The Atrial Sensing to Reduce Inappropriate Defibrillation (ASTRID) study examined the utility of enhanced detection algorithms [29]. In ASTRID, patients with dual-chamber devices were randomized to rate-only detection versus an enhanced detection algorithm that included rate stability and ventricular greater than atrial rate (V 4 A). The time to first inappropriate therapy was greater in the enhanced detection arm and there were fewer high-energy shocks in this arm. A comparison of physician tailoring of ICD programing versus standardized ICD programing was performed in the
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Comparison of Empiric to Physician-Tailored Programming of Implantable Cardioverter–Defibrillators (EMPIRIC) study [30]. The standardized settings were non-inferior with no differences in mortality. Standardized settings included increased use of VT zones with SVT discriminators and ATP, confirming the findings of ASTRID and Pain-FREE Rx II. The Primary Prevention Parameters Evaluation (PREPARE) study similarly compared a set of standardized ICD settings to individual tailored settings, with benefit observed in the standardized group [31]. The standardized settings again emphasized use of SVT discrimination and ATP. Additionally, it utilized a higher heart rate threshold for tachycardia detection (182 bpm) and prolonged detection duration before delivering therapy. Finally, the Multicenter Automatic Defibrillator Implantation Trial-Reduce Inappropriate Therapy (MADIT-RIT) study [32] compared a high-rate arm in which tachycardia therapy was delivered only for rates 4200 bpm; a delayed therapy arm in which tachycardia was sustained for 460 s for rates of 170–199 bpm, 12 s for rates 200–250 bpm, and 2.5 s for rates 4250 bpm; and a conventional therapy arm. In both the high-rate and delayed therapy arms, patients received fewer inappropriate device therapies, and surprisingly in the high-rate arm, reduced mortality was seen. These findings have led to simpler ICD programing, particularly in primary prevention patients, using much higher-rate cutoffs than used in prior clinical practice and have called into question the need for dual-chamber detection and other SVT discriminators tested in the earlier studies mentioned above. An additional important question with ICD implantation has been the role of routine defibrillation threshold (DFT) testing at the time of ICD implantation. Historically, this has been performed to establish appropriate effectiveness and safety margins, which was particularly useful early in ICD placement when performance was less predictable. Despite years of routine DFT testing, there was limited evidence to support its efficacy. The Shockless Implant Evaluation (SIMPLE) study randomized patients undergoing new ICD implantation to with or without DFT testing [33]. Powered for non-inferiority, the study showed no difference in arrhythmic death with similar safety between groups. These findings support the practice of primary prevention ICD implantation without DFT testing, at least in the setting of a standard left pectoral implant with a standard trans-venous lead.
ICDs in heart failure therapy Ventricular dyssynchrony from conduction abnormalities increases mortality in heart failure. In addition to their role in arrhythmia detection and treatment, ICDs with biventricular pacing may reverse LV remodeling, reduce heart failure hospitalizations, and improve NYHA functional class [34]. A significant number of patients receiving primary prevention ICDs also meet indications for cardiac resynchronization therapy (CRT) with biventricular pacing. The Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) study established benefit with CRT alone in the treatment of severe heart failure and incremental benefit when CRT was combined with a defibrillator (CRT-D) [35]. The
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Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT) study demonstrated reduced death or heart failure events in those with NYHA Class I or II heart failure, EF r 30%, and QRS duration Z130 ms [36]. The benefit of CRT-D over ICD alone has also been established in moderate and severe heart failure [37,38]. Current guidelines specify the type and nature of QRS width, with greatest support for QRS width Z150 ms and left bundle branch block morphology [26]. Given the findings of these studies, physicians must consider QRS duration and NYHA heart failure class at the time of ICD implantation to assess the potential efficacy of CRT. Additionally, heart failure patients with ICDs should be monitored over time for consideration for upgrade to a CRT-D device.
ICDs in disease management The expanding indications for ICD and the complexity of the devices require a multi-disciplinary approach to routine monitoring of arrhythmia detection, the technical aspects of the device, and the course of the underlying disease. Current management involves scheduled routine follow-up in-person. This periodic interval assessment can lead to delays in recognition of changes in clinical status. ICDs have the capability for relaying useful information already stored in the device to the providers via remote telemetry. This provides continuous surveillance and early recognition of potential arrhythmias or device-related problems and could possibly reduce unnecessary follow-up visits. In recent years, major ICD manufacturers have developed remote monitoring technology, including Merlin (St Jude Medical), CareLink (Medtronic), and LATITUDE (Boston Scientific). These systems have the ability to remotely relay information such as heart rate, patient activity level, intra-thoracic impedance for the detection of fluid accumulation, and arrhythmia episodes. Safety and ease of use have been established in small clinical trials [39]. The Evolution of Management Strategies of Heart Failure Patients with Implantable Defibrillators (EVOLVO) study randomized 200 heart failure patients to optimal medical therapy versus remote monitoring using the CareLink system [40]. Remote monitoring was associated with decreased emergency department and urgent clinic visits for heart failure and a reduction in time from ICD alert to clinician review of the data. In the preliminary presentation of data from the Patient Related Determinants of ICD Remote Monitoring Utilization and Outcomes (PREDICT-RM) study, utilizing LATITUDE, significant reductions in mortality and heart failure hospitalizations were observed [41]. Though such remote monitoring features are now a part of many ICDs currently being implanted, remote monitoring is not yet a part of heart failure guidelines and more clinical data is needed to elucidate their role in heart failure management.
Future directions In a just a few decades, the ICD has progressed from an idea to a well-proven means of improving survival in patients who have survived or are at risk for sudden cardiac death. While
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remote monitoring is only one aspect of an evolving strategy in how we manage patients with complex cardiac conditions with implantable devices, there are multiple areas of ongoing investigation in improving on this technology. The subcutaneous ICD (S-ICD) has been an area of significant interest. The S-ICD was designed to help overcome the challenges of a trans-venous system such as infection, thrombus formation, and difficulty of extraction. The safety and efficacy of these devices has been studied in small nonrandomized clinical trials [42,43]. Based on these studies, the S-ICD gained FDA approval for patients who do not require bradycardia pacing, ATP, or CRT. While much focus has been placed on optimal programing of ICDs to reduce appropriate and inappropriate shocks, there is significant interest in developing adjunctive therapies to an ICD to reduce ventricular arrhythmias and need for device therapy. Catheter ablation of VT has the ability to terminate incessant VT and reduce VT burden [44]. Finally, while ICD implantation is mostly utilized in the setting of impaired LV function, only a small percentage of those with implanted ICDs will ever benefit from device therapy. Much work is still required to better define and understand the patient groups most likely to benefit from ICDs, both to reduce the number of devices implanted that never deliver appropriate therapy and to increase the number of lives saved.
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McAlister FA, Ezekowitz J, Hooton N, Vandermeer B, Spooner C, Dryden DM, et al. Cardiac resynchronization therapy for patients with left ventricular systolic dysfunction: a systematic review. J Am Med Assoc 2007;297:2502–14. Bristow MR, Saxon LA, Boehmer J, Krueger S, Kass DA, De Marco T, et al. Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med 2004;350:2140–50. Moss AJ, Brown MW, Cannom DS, Daubert JP, Estes M, Foster E, et al. Multicenter automatic defibrillator implantation trial-cardiac resynchronization therapy (MADIT-CRT): design and clinical protocol. Ann Noninvasive Electrocardiol 2005;10:34–43. Tang AS, Wells GA, Talajic M, Arnold MO, Sheldon R, Connolly S, et al. Cardiac-resynchronization therapy for mild-to-moderate heart failure. N Engl J Med 2010;363: 2385–95. Young JB, Abraham WT, Smith AL, Leon AR, Lieberman R, Wilkoff B, et al. Combined cardiac resynchronization and implantable cardioversion defibrillation in advanced chronic heart failure: the MIRACLE ICD Trial. J Am Med Assoc 2003;289:2685–94. Marzegalli M, Lunati M, Landolina M, Perego GB, Ricci RP, Guenzati G, et al. Remote monitoring of CRT–ICD: the multicenter Italian CareLink evaluation—ease of use, acceptance, and organizational implications. Pacing Clin Electrophysiol 2008;31:1259–64. Landolina M, Perego GB, Lunati M, Curnis A, Guenzati G, Vicentini A, et al. Remote monitoring reduces healthcare use and improves quality of care in heart failure patients with implantable defibrillators: the evolution of management strategies of heart failure patients with implantable defibrillators (EVOLVO) study. Circulation 2012;125:2985–92. Akar JG. Patient related determinants of ICD remote monitoring utilization and outcomes (PREDICT-RM). In: Proceedings of heart rhythm society scientific sessions 2014; 2014. Bardy GH, Smith WM, Hood MA, Crozier IG, Melton IC, Jordaens L, et al. An entirely subcutaneous implantable cardioverter–defibrillator. N Engl J Med 2010;363:36–44. Weiss R, Knight BP, Gold MR, Leon AR, Herre JM, Hood M, et al. Safety and efficacy of a totally subcutaneous implantablecardioverter defibrillator. Circulation 2013;128:944–53. Zipes DP, Camm AJ, Borggrefe M, Buxton AE, Chaitman B, Fromer M, et al. ACC/AHA/ESC 2006 Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: a report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (writing committee to develop Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Circulation 2006;114:e385–484.
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Available online at www.sciencedirect.com
www.elsevier.com/locate/tcm
The implantable cardioverter–defibrillator: An update Jared D. Miller, Omair Yousuf, and Ronald D. Bergern Department of Medicine, Johns Hopkins University, Baltimore, MD
abstra ct The implantable cardioverter–defibrillator (ICD) provides life-saving therapy to prevent sudden cardiac death. ICDs have been implanted in millions of patients worldwide since the first human implant in 1980. Clinical trials have helped establish guidelines for ICD implantation in primary and secondary prevention of sudden cardiac death. Recent trials have also tested and compared various programing strategies to avoid unnecessary shocks and improve survival among ICD recipients. ICDs may also assist with monitoring for heart failure management. In this review, we discuss the clinical science to date that has helped define the role of ICDs in current practice. & 2015 Elsevier Inc. All rights reserved.
Brief history of the ICD The implantable cardioverter–defibrillator (ICD) has emerged as an important tool for the prevention of sudden cardiac death (SCD) in selected patients. SCD frequently occurs from sustained rapid ventricular tachycardia (VT) or VT that degenerates into ventricular fibrillation (VF). Claude Beck is credited with saving the first human life with defibrillation of VF in an operating room in 1947 [1]. While management of ventricular arrhythmias in the hospitalized setting improved with the advent of coronary care units in the 1960s, the majority of SCD events occur outside medical facilities and resuscitative efforts for out-of-hospital cardiac arrest are abysmal, with only an estimated 8% of patients surviving to hospital discharge [2]. These early accomplishments, coupled with the enormous challenge of preventing sudden death in the outpatient setting, paved the road for the landmark work and contributions by Dr. Michel Mirowski and colleagues. Despite significant skepticism in the medical community during their initial efforts, the first human implantation of an ICD was performed in 1980 at Johns Hopkins Hospital [3].
Over the last three decades, significant progress has been made in ICD design and programing to maximize therapeutic benefit and minimize patient discomfort. Today, ICD therapy is the standard of care in the primary and secondary prevention of sudden cardiac death.
Clinical science/trials Current guidelines support the use of ICD therapy for primary and secondary prevention of SCD in specific clinical situations [4]. In the context of ICD therapy, primary prevention is defined as interventions performed to prevent SCD, whereas secondary prevention refers to therapies aimed at preventing SCD in those who have already experienced life-threatening VT/VF. These guidelines are well informed by large randomized clinical trials demonstrating the efficacy of ICD therapy. This review will summarize the landmark primary and secondary prevention trials and their implications in current practice.
Dr. Berger is a consultant for Boston Scientific Corp. The other authors have indicated there are no conflicts of interest. n Correspondence to: Ronald D. Berger, MD, PhD, Johns Hopkins Hospital, Halsted 570, 600 N Wolfe St, Baltimore, MD 21287. Tel.: þ1 410 614 2751; fax: þ1 410 502 4854. E-mail address: [email protected] (R.D. Berger). http://dx.doi.org/10.1016/j.tcm.2015.01.015 1050-1738/& 2015 Elsevier Inc. All rights reserved.
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Secondary prevention Patients with prior cardiac arrest are at significantly higher risk of recurrent arrest and SCD. With the exception of amiodarone, anti-arrhythmic drugs have failed to improve survival or reduce the frequency of ventricular arrhythmias. The first landmark study, Anti-arrhythmics Versus Implantable Defibrillators (AVID) study, enrolled patients with prior resuscitation for VF or cardioversion for sustained ventricular tachycardia (VT) and randomized them to ICD therapy or Class III anti-arrhythmics (primarily amiodarone) [5]. There was a significant reduction in the primary endpoint of mortality in the ICD group at three-year follow-up. Subgroup analyses demonstrated the greatest benefit in those with significantly reduced left ventricular (LV) systolic function. The Canadian Implantable Defibrillator Study (CIDS) randomized patients with resuscitated VT or VF or unmonitored syncope to an ICD versus amiodarone [6]. A nonsignificant but consistent reduction in all-cause and arrhythmic mortality was observed with ICD therapy. Similar to CIDS, the Cardiac Arrest Study Hamburg (CASH) observed a nonsignificant reduction in mortality in ICD therapy compared to amiodarone/metoprolol therapy in patients with a history of cardiac arrest from ventricular arrhythmia [7]. Metaanalyses of these three studies demonstrated significant reduction in all-cause and arrhythmic mortality with ICD therapy [8]. The summation of these studies has led to current practice guidelines in which ICD therapy is indicated for survivors of cardiac arrest due to VF or hemodynamically unstable sustained VT, irrespective of LV function, following an evaluation to define the cause of the arrhythmia and exclusion of reversible causes. Notably, in the AVID registry, patients with a transient or correctable cause of VT/VF, including recent myocardial infarction, acute ischemia, drug overdose, or severe electrolyte imbalance who did not receive an ICD surprisingly had high subsequent mortality [9]. Thus, ICD therapy may be appropriate even in selected cases when the underlying cause of the arrhythmia is thought to be correctable.
Primary prevention Survivors of out-of-hospital cardiac arrest represent a very small fraction of those who may benefit from an ICD. There is a strong desire to identify patients at highest risk and treat them prophylactically with ICD therapy. A number of studies have helped establish the role of a primary prevention ICD in both ischemic and non-ischemic cardiomyopathy. The Multicenter Unsustained Tachycardia Trial (MUSTT) randomized patients with prior MI, left ventricular ejection fraction (LVEF) r40%, documented non-sustained VT (NSVT), and inducible VT to electrophysiology (EP) study-guided management versus standard medical care [10]. This study demonstrated survival benefit only in patients within the EP study-guided therapy arm who received an ICD, whereas those receiving anti-arrhythmic drugs did not show similar benefit. Similarly, the Multicenter Automatic Defibrillator Implantation Trial (MADIT) randomized patients with prior MI, LVEF r35%, documented NSVT, and inducible VT at EP study, which was not suppressible with procainamide, to ICD versus
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medical therapy (primarily amiodarone) [11]. There was a relative 54% all-cause mortality reduction in the ICD group. The follow-up MADIT II study was performed to evaluate the role of an ICD in a broader population without the need for ambient or inducible arrhythmia at EP study prior to enrollment [12]. This landmark study randomized 1232 patients with a prior MI and LVEF r30% to an ICD versus conventional medical therapy. ICD therapy was associated with a 49% relative reduction in all-cause mortality. To date, the largest study of ICD therapy in primary prevention heart failure patients was the Sudden Cardiac Death in Heart Failure study (SCD-HeFT), which randomized 2521 patients with NYHA Class II or III heart failure and LVEF r35% with ischemic or non-ischemic substrate, to ICD, amiodarone, or placebo [13]. There was no difference in mortality between the amiodarone and placebo groups, but there was a 23% relative reduction in mortality in the ICD arm with an absolute risk reduction of 7.2%. The benefit of ICD therapy was similar in ischemic and non-ischemic substrates, and greater benefit was seen in those with NYHA Class II symptoms as opposed to those with NYHA Class III heart failure. The Cardiomyopathy Trial (CAT), Amiodarone versus Implantable Defibrillator (AMIOVIRT), and Defibrillators in Non-Ischemic Cardiomyopathy Treatment Evaluation (DEFINITE) studies were limited to patients with non-ischemic cardiomyopathies [14–16]. While several of these small studies failed to show any survival benefit with ICD therapy, the DEFINITE study, which included patients with non-ischemic dilated cardiomyopathy, LVEF o 36%, and premature ventricular contractions or NSVT, demonstrated a trend toward reduction in total mortality and a significant reduction in arrhythmic death with ICD therapy. A meta-analysis confirmed a significant reduction in mortality with ICD therapy in patients with non-ischemic cardiomyopathy [17]. The findings of these studies, in combination with the results of SCD-HeFT, have established the role of ICD therapy in this population. While most studies to date have expanded the role of ICD therapy in clinical practice, ICD therapy in selected populations has demonstrated a lack of efficacy. In the Coronary Artery Bypass Graft (CABG) Patch trial, patients with a LVEF r35% and abnormalities on signal-averaged electrocardiogram, who underwent revascularization with elective coronary bypass surgery, were randomized to ICD therapy or conventional therapy [18]. There was no difference in overall mortality between the two groups. Similarly, the Defibrillator in Acute Myocardial Infarction (DINAMIT) trial randomized patients with LV dysfunction and impaired cardiac autonomic function, who were 6–40 days post-MI, to ICD versus no ICD therapy showed no difference in overall mortality [19]. ICD implantation after MI was also evaluated by the Immediate Risk Stratification Improves Survival (IRIS) study, in which patients within 5–31 days after a MI with LVEF r 40%, heart rate greater than 90 beats per minute (BPM) or nonsustained VT on Holter monitoring were randomized to ICD or standard medical therapy [20]. ICD therapy conferred no additional benefit in mortality reduction. The totality of these studies has solidified recommendations for ICDs not to be implanted in the peri-MI or peri-revascularization period.
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ICDs in other high-risk populations The majority of studies in ICD therapy have been focused on those with structural heart disease and reduced LVEF, which constitute the largest group of patients at risk. However, numerous other conditions are known to be associated with an increased risk of sudden cardiac death. Though these populations are too small for large randomized trials, observational analyses have helped define cohorts that may benefit from ICDs. One such high-risk group includes those with inherited abnormalities of ion channels, including longQT syndrome, Brugada syndrome, and catecholaminergic polymorphic VT. Another such group includes those with structural heart disease such as hypertrophic cardiomyopathy (HCM) or arrhythmogenic right ventricular dysplasia/ cardiomyopathy (ARVD/C) [21]. The risk factors of SCD in HCM populations have been well studied in observational trials. ICD therapy is indicated in those with HCM and at least one of the following major risk factors: SCD in a first-degree relative, maximal LV wall thickness Z30 mm, and unexplained syncope [22]. There is a clear role for ICD therapy for secondary prevention in ARVD/C and other inherited high-risk conditions. While the predictive markers for SCD in ARVD/C are still being elucidated [23–25], a primary prevention ICD is recommended for those with ARVD/C who have at least one additional risk factor [4].
Current guidelines Consensus guideline statements have largely followed the results of the clinical trials discussed above. The 2008 ACC/ AHA/HRS guideline statement, which was updated in 2012, has been an important clinical guide both for physicians and for informing reimbursement for ICD expenses [4,26]. As per the results of AVID, CIDS, and CASH, ICDs are a Class I indication in secondary prevention for survivors of VF or hemodynamically unstable VT without a readily reversible cause. Additional Class I indications in secondary prevention include those with structural heart disease and sustained VT, or syncope of unknown origin and VT or VF induced at EP study. In primary prevention, an ICD is indicated in those with LVEF r 35%, NYHA Class II or III heart failure, and those who are at least 40 days post-MI. This guideline is consistent with the inclusion criteria of SCD-HeFT and is inclusive of the findings of DINAMIT and IRIS in post-MI patients. While most patients require a LVEF of r35% to be eligible for primary prevention ICD therapy, post-MI patients with NYHA Class I heart failure may have a LVEF of 30%—a recommendation based on the inclusion criteria of the MADIT II study. The final Class I indication for ICD implantation arises from the results of MUSTT, which included patients with prior MI and LVEF r 40%, non-sustained VT who have inducible VT, or sustained VF during an EP study. A number of Class IIa indications exist for commonly encountered situations in which the evidence is not as robust. ICD therapy is reasonable in those with unexplained syncope, LV dysfunction, and non-ischemic dilated cardiomyopathy (DCM) or those with sustained VT and near-normal LV
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function. Class IIa indications also include inherited abnormalities of ion channels and structural heart disease such as HCM or ARVD/C. ICD therapy is not recommended in certain populations (Class III indications), including those with life expectancy less than one year, NYHA Class IV heart failure, significant psychiatric illness that would be exacerbated by device implantation or prevent routine follow-up, VF or VT due to a reversible disorder, or ventricular arrhythmias that are amenable to surgical or catheter ablation. Despite the existence of numerous clinical trials in ICD therapy, many nuanced clinical situations exist, which have not been evaluated in randomized trials and are therefore not discussed in current guidelines. This has become especially important with regards to reimbursement of ICD implantation. A recently published expert consensus document outlines various clinical scenarios outside of guideline-directed recommendations [27]. These include device therapy recommendations for patients within 40 days of a MI or within 90 days of revascularization who have an alternate indication for device therapy, such as pacing for bradyarrhythmia. Because scenarios such are these and many others will likely never be evaluated in large-scale clinical trials, such expert consensus statements are important in helping to define appropriate ICD use.
ICD Programing In addition to critical progress in identifying patient populations who benefit from ICD therapy, important clinical studies have also provided guidance in optimization of ICD programing. A number of randomized trials have tested different tachycardia detection strategies and the use of available therapies to help optimize ICD benefit while minimizing side effects, most notably unnecessary shocks. Both appropriate and inappropriate ICD shocks have been strongly associated with psychological effects and reduced quality of life [21]. The efficacy of anti-tachycardia pacing (ATP) to terminate VT has been established in clinical trials. The Pacing Fast Ventricular Tachycardia Reduces Shock Therapies (Pain-FREE Rx II) trial demonstrated the safety and effectiveness of ATP in fast VT [28]. Patients were randomized to ICD programing with either traditional shock therapy for rates 4200 bpm versus ATP followed by a shock if ineffective. There was no difference between groups in episode duration, syncope, or sudden cardiac death. The ATP arm had fewer shocks delivered and ATP therapy was successful in terminating 72% of VT episodes. Regarding arrhythmia detection, ICDs were initially programed to detect tachycardia on the basis of heart rate alone. The Atrial Sensing to Reduce Inappropriate Defibrillation (ASTRID) study examined the utility of enhanced detection algorithms [29]. In ASTRID, patients with dual-chamber devices were randomized to rate-only detection versus an enhanced detection algorithm that included rate stability and ventricular greater than atrial rate (V 4 A). The time to first inappropriate therapy was greater in the enhanced detection arm and there were fewer high-energy shocks in this arm. A comparison of physician tailoring of ICD programing versus standardized ICD programing was performed in the
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Comparison of Empiric to Physician-Tailored Programming of Implantable Cardioverter–Defibrillators (EMPIRIC) study [30]. The standardized settings were non-inferior with no differences in mortality. Standardized settings included increased use of VT zones with SVT discriminators and ATP, confirming the findings of ASTRID and Pain-FREE Rx II. The Primary Prevention Parameters Evaluation (PREPARE) study similarly compared a set of standardized ICD settings to individual tailored settings, with benefit observed in the standardized group [31]. The standardized settings again emphasized use of SVT discrimination and ATP. Additionally, it utilized a higher heart rate threshold for tachycardia detection (182 bpm) and prolonged detection duration before delivering therapy. Finally, the Multicenter Automatic Defibrillator Implantation Trial-Reduce Inappropriate Therapy (MADIT-RIT) study [32] compared a high-rate arm in which tachycardia therapy was delivered only for rates 4200 bpm; a delayed therapy arm in which tachycardia was sustained for 460 s for rates of 170–199 bpm, 12 s for rates 200–250 bpm, and 2.5 s for rates 4250 bpm; and a conventional therapy arm. In both the high-rate and delayed therapy arms, patients received fewer inappropriate device therapies, and surprisingly in the high-rate arm, reduced mortality was seen. These findings have led to simpler ICD programing, particularly in primary prevention patients, using much higher-rate cutoffs than used in prior clinical practice and have called into question the need for dual-chamber detection and other SVT discriminators tested in the earlier studies mentioned above. An additional important question with ICD implantation has been the role of routine defibrillation threshold (DFT) testing at the time of ICD implantation. Historically, this has been performed to establish appropriate effectiveness and safety margins, which was particularly useful early in ICD placement when performance was less predictable. Despite years of routine DFT testing, there was limited evidence to support its efficacy. The Shockless Implant Evaluation (SIMPLE) study randomized patients undergoing new ICD implantation to with or without DFT testing [33]. Powered for non-inferiority, the study showed no difference in arrhythmic death with similar safety between groups. These findings support the practice of primary prevention ICD implantation without DFT testing, at least in the setting of a standard left pectoral implant with a standard trans-venous lead.
ICDs in heart failure therapy Ventricular dyssynchrony from conduction abnormalities increases mortality in heart failure. In addition to their role in arrhythmia detection and treatment, ICDs with biventricular pacing may reverse LV remodeling, reduce heart failure hospitalizations, and improve NYHA functional class [34]. A significant number of patients receiving primary prevention ICDs also meet indications for cardiac resynchronization therapy (CRT) with biventricular pacing. The Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) study established benefit with CRT alone in the treatment of severe heart failure and incremental benefit when CRT was combined with a defibrillator (CRT-D) [35]. The
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Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT) study demonstrated reduced death or heart failure events in those with NYHA Class I or II heart failure, EF r 30%, and QRS duration Z130 ms [36]. The benefit of CRT-D over ICD alone has also been established in moderate and severe heart failure [37,38]. Current guidelines specify the type and nature of QRS width, with greatest support for QRS width Z150 ms and left bundle branch block morphology [26]. Given the findings of these studies, physicians must consider QRS duration and NYHA heart failure class at the time of ICD implantation to assess the potential efficacy of CRT. Additionally, heart failure patients with ICDs should be monitored over time for consideration for upgrade to a CRT-D device.
ICDs in disease management The expanding indications for ICD and the complexity of the devices require a multi-disciplinary approach to routine monitoring of arrhythmia detection, the technical aspects of the device, and the course of the underlying disease. Current management involves scheduled routine follow-up in-person. This periodic interval assessment can lead to delays in recognition of changes in clinical status. ICDs have the capability for relaying useful information already stored in the device to the providers via remote telemetry. This provides continuous surveillance and early recognition of potential arrhythmias or device-related problems and could possibly reduce unnecessary follow-up visits. In recent years, major ICD manufacturers have developed remote monitoring technology, including Merlin (St Jude Medical), CareLink (Medtronic), and LATITUDE (Boston Scientific). These systems have the ability to remotely relay information such as heart rate, patient activity level, intra-thoracic impedance for the detection of fluid accumulation, and arrhythmia episodes. Safety and ease of use have been established in small clinical trials [39]. The Evolution of Management Strategies of Heart Failure Patients with Implantable Defibrillators (EVOLVO) study randomized 200 heart failure patients to optimal medical therapy versus remote monitoring using the CareLink system [40]. Remote monitoring was associated with decreased emergency department and urgent clinic visits for heart failure and a reduction in time from ICD alert to clinician review of the data. In the preliminary presentation of data from the Patient Related Determinants of ICD Remote Monitoring Utilization and Outcomes (PREDICT-RM) study, utilizing LATITUDE, significant reductions in mortality and heart failure hospitalizations were observed [41]. Though such remote monitoring features are now a part of many ICDs currently being implanted, remote monitoring is not yet a part of heart failure guidelines and more clinical data is needed to elucidate their role in heart failure management.
Future directions In a just a few decades, the ICD has progressed from an idea to a well-proven means of improving survival in patients who have survived or are at risk for sudden cardiac death. While
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remote monitoring is only one aspect of an evolving strategy in how we manage patients with complex cardiac conditions with implantable devices, there are multiple areas of ongoing investigation in improving on this technology. The subcutaneous ICD (S-ICD) has been an area of significant interest. The S-ICD was designed to help overcome the challenges of a trans-venous system such as infection, thrombus formation, and difficulty of extraction. The safety and efficacy of these devices has been studied in small nonrandomized clinical trials [42,43]. Based on these studies, the S-ICD gained FDA approval for patients who do not require bradycardia pacing, ATP, or CRT. While much focus has been placed on optimal programing of ICDs to reduce appropriate and inappropriate shocks, there is significant interest in developing adjunctive therapies to an ICD to reduce ventricular arrhythmias and need for device therapy. Catheter ablation of VT has the ability to terminate incessant VT and reduce VT burden [44]. Finally, while ICD implantation is mostly utilized in the setting of impaired LV function, only a small percentage of those with implanted ICDs will ever benefit from device therapy. Much work is still required to better define and understand the patient groups most likely to benefit from ICDs, both to reduce the number of devices implanted that never deliver appropriate therapy and to increase the number of lives saved.
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