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Indications for Pacing
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Cardiac pacing was initially developed to address the problem of bradyarrhythmia, particularly caused by AV block and sinus node dysfunction (SND). These continue to constitute the primary indications for consideration for pacing, although pacing for neurocardiogenic syncope and special situations (eg, postcardiac transplant, neuromuscular disease, sleep apnea, or infiltrative disease) has grown. Pacing for the termination of arrhythmia (or anti-tachycardia pacing [ATP]) is almost exclusively employed in combination pacemaker-defibrillator devices in the modern setting. The clinical guidelines for consideration of pacing were recently outlined by a collaboration between the American College of Cardiology Foundation (ACCF), American Heart Association (AHA), and Heart Rhythm Society (HRS).7
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Class I recommendations for pacing for SND hinge primarily on the presence of symptoms, along with class II consideration for pacing in patients with heart rate < 40 bpm while awake, with (class IIa) or without (class IIb) clear symptomology associated with bradycardia (Table 89–1). SND may be caused by either intrinsic disease or sinoatrial exit block, and also includes sinus pause after cessation of atrial tachyarrhythmia (Fig. 89–2).
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Indications for pacing in acquired AV block attempt to discriminate between sites of block in the cardiac conduction system. Broadly, block above the AV node is considered lower risk than below the node (ie, infranodal block) (Fig. 89–3) because of the relative instability of escape rhythms emanating from below the AV junction. This is particularly salient in patients with stigmata of other His-Purkinje disease, such as bundle branch block (BBB) or fascicular block. In addition, AV block at any level may contribute to the risk of ventricular arrhythmia through a pause-dependent mechanism. The indications for pacing in acquired AV block take into account the site of block and, similar to recommendations for SND, suggest pacing in patients with symptomatic bradycardia < 40 bpm (including HF), for those who require medical therapy and are at risk for bradycardia, and in those at risk for significant pauses (> 3 seconds). In contrast to indications for SND, however, pacing is recommended even in asymptomatic patients if infranodal block (ie, intra-His or infra-His) is suspected (Table 89–2). Patients with alternating BBB (ie, right BBB [RBBB] alternating with left BBB [LBBB], or RBBB alternating with associated left anterior fascicular block and left posterior fascicular block), or with chronic bifascicular block associated and type 2 second-degree or advanced AV block, also meet a class I indication for pacing, irrespective of symptoms. AV block is also frequently a sequel of ST-segment elevation myocardial infarction (MI), and is associated with poorer prognosis overall. Generally, patients with inferior MI demonstrate nodal AV block that is transient, whereas anterior MI may cause direct infranodal and fascicular ischemia leading to higher degree of persistent AV block. An electrophysiology (EP) study may be necessary in differentiating the site of block in patients where the site of block is uncertain (class I indication; level of evidence [LOE] B).
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Pacing in Hypersensitive Carotid Sinus Syndrome or for Neurocardiogenic Syncope
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Pacing in these conditions is generally reserved for patients in whom a cardioinhibitory reflex (as opposed to vasodepressor response) predominates with respect to their syndromes. These include patients in whom carotid sinus stimulation induces ventricular asystole for > 3 seconds and is associated with syncope (class I indication; LOE C). The indications are downgraded in patients with a hypersensitive cardioinhibitory response without clear, provocative events (class IIa; LOE C), and for those with significantly symptomatic neurocardiogenic syncope and bradycardia documented spontaneously (as with event monitoring or implantable loop monitor) or during tilt table testing (class IIb; LOE B).
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Pacing in Specific Conditions
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Specific conditions that merit indication for pacing include patients who have undergone cardiac transplant, patients with neuromuscular diseases such as myotonic dystrophy and Emery-Dreifuss syndrome, sleep apnea, cardiac sarcoidosis, and patients with hypertrophic cardiomyopathy (HCM) and evidence of dynamic left ventricular outflow tract (LVOT) obstruction. In addition to standard indications, patients postcardiac transplant may benefit from pacing even for relative bradycardia if it is prolonged or recurrent (class IIb; LOE C), and asymptomatic patients with neuromuscular disease with prolonged His-Ventricular (HV) interval or abnormal resting electrocardiogram (ECG) may also benefit from pacing. Pacing indications for nocturnal bradyarrhythmia in patients with sleep apnea that remains persistent despite continuous positive airway pressure have not been established.7,8 With respect to cardiac sarcoidosis, a recent expert consensus statement of the HRS suggested that, in addition to the accepted guidelines, there is a class IIa indication for device implantation even in patients with transient AV block owing to the unpredictable nature of the disease and its variable response to immunosuppression.9 After initial exuberance for the role of dual-chamber pacing to alter septal contraction timing and reduce LVOT gradients for obstructive HCM, subsequent randomized crossover studies have not shown consistent benefit. Permanent pacing is now reserved only for medically refractory patients with obstructive HCM in whom septal reductive therapy is not possible (class IIb; LOE B).10
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Seminal Pacemaker Trials
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Beginning in the late 1950s, the original indications for pacing consisted of treatment for malignant bradyarrhythmias. Given that the benefits of cardiac pacing were imminent and lifesaving (eg, pacing to prevent ventricular asystole), use of pacing versus sham was not studied for these indications in controlled trials. With the development of dual-chamber and multisite pacing systems, there has been randomized investigation with respect to pacemaker device type and mode selection. The evidence base to guide mode selection was recently reviewed in an expert consensus jointly released by the HRS and the ACCF11 along with a systematic review commissioned by the National Institute for Health Research.12 Observations regarding the seminal trials supporting these recommendations, as well as emerging technology in so-called “leadless” pacing, will briefly be reviewed here.
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Pacing Mode Selection for SND
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There have been four major randomized trials comparing single or dual-chamber pacing for patients with bradycardia secondary to isolated sinoatrial dysfunction in the absence of AV block.13,14,15,16 There are multiple possible approaches to pacing for these patients, including single-chamber atrial-only pacing, single-chamber ventricular-only pacing, or dual-chamber atrial and ventricular pacing (Fig. 89–4). The first large study seeking to answer this question was conducted by Andersen and associates at a single center in Denmark and has been referred to subsequently as the Danish Study.16 In the study, 225 consecutive patients with sick-sinus syndrome were randomized to single-chamber atrial or single-chamber ventricular pacing. Mortality was not significantly different between the two groups at 40 months, but was significantly lower in patients receiving atrial-only pacing at 5.5 years (hazard ratio [HR] 0.66, P = .045).17 Incidence of atrial fibrillation (AF) was also significantly less common in patients who were atrially paced and, interestingly, the rate of thromboembolic events—specifically stroke or peripheral arterial embolism—was lower in patients receiving single-chamber atrial pacing (17% vs 5%, P = .0083). In order to enroll, patients were required to demonstrate a PQ interval of less than 220 ms and atrial pacing with 1:1 AV conduction was required at a rate of at least 100 bpm. With these criteria, a low rate of progression of AV block was noted (0.6% per year).18 Single-chamber atrial versus dual-chamber atrial and ventricular pacing was next studied in another randomized study of 177 patients by Nielsen et al.15 In contrast to ventricular-only pacing, there was no difference in this study with respect to morality, thromboembolism, or HF, but dual-chamber pacing was associated with increased left atrial size and reduced LV fractional shortening versus atrial-only pacing.
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The matter of whether atrial-only or dual-chamber pacing is superior in SND was evaluated most comprehensively in DANPACE. Investigators at 20 European centers randomized 1415 patients with isolated SND and no AV block or BBB to single or dual-chamber rate-adaptive pacemakers.13 The primary outcome of all-cause death was no different between the two groups, nor was there a difference with respect to secondary end points of incidence of stroke or HF. Surprisingly, and in stark contrast to prior randomized studies of atrial versus ventricular-only or dual-chamber pacing, atrial rate-adaptive pacing was associated with an increased risk of paroxysmal AF (HR 1.27, P = .024) in DANPACE, although permanent AF was not different. The mechanism for this difference is unclear; patients were programmed to paced AV delays of ≤ 220 ms, which may have promoted better AV synchrony. Perhaps more importantly, however, the reoperation rate was significantly higher in this multicenter investigation of single-chamber devices (HR 1.99, P < .0001), and was driven by the need for change of pacing mode as a result of progression of heart block (at a mean rate of 1.7% per year, close to three times the rate of the Danish study). Any pacemaker reoperation is associated with a risk of infection or extraction, and these considerations factored into the class I recommendation for consideration of dual-chamber over single-chamber atrial pacing in SND.11
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Importantly, the largest randomized pacemaker study for isolated SND was the Mode Selection Trial (MOST), although it did not look at atrial-only pacing systems. The trial randomized a total of 2010 patients to either dual-chamber (atrial and ventricular) or single-chamber (ventricular-only) pacing.14 Neither the primary end point of death from any cause or nonfatal stroke, nor the secondary end point—a composite of death, stroke, or HF hospitalization—differed between patients assigned to dual-chamber versus ventricular-only pacing. Incidence of AF was less common with dual-chamber pacing (HR 0.79, P = .008), HF scores were better (P < .0001), as were quality of life metrics. Importantly, close to one-third of patients assigned to ventricular pacing crossed-over to dual-chamber pacing. This was driven by incidence of the pacemaker syndrome in half of all crossovers. Notable here is that MOST had a strict definition for pacemaker syndrome, requiring documentation of both symptoms of dyspnea or syncope along with demonstration of ventriculoatrial (VA) conduction or blood pressure (BP) reduction of 20 mm Hg or more during ventricular-only pacing. In addition, there was signal regarding the deleterious effect of right ventricular (RV) pacing, as cumulative percentage of RV pacing (cum%VP) was associated with an increased risk of HF or AF in patients with both dual-chamber (HR 2.99, P = .024 for cum%VP > 40) and single-chamber (HR 2.56, P = .0007, cum%VP > 80) devices.19 These findings were later further validated in the SAVE-PACe trial, which randomized 1065 patients with SND to dual-chamber devices programmed to deliver conventional AV pacing or to implement device-based algorithms to minimize ventricular pacing.20 Conventional pacing systems with ~99% ventricular pacing versus those designed to minimize pacing (mean 9.1%) were associated with 40% increased risk of persistent AF (P = .0009), but no differences in mortality.
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Pacing Mode Selection for AV Block
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There have been three large randomized trials investigating the role of pacing mode in patients with AV block.21,22,23 Two of these trials, the Pacemaker Selection in the Elderly (PASE) study and the Canadian Trial of Physiologic Pacing (CTOPP), enrolled patients with SND and AV block. The largest and most recent, the United Kingdom Pacing and Cardiovascular Events (UKPACE) study, was focused on the question of how best to pace patients with AV block only.
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PASE was a single-blind, randomized study of ventricular versus dual-chamber pacing in patients over the age of 65 years.21 Of 407 patients studied, 201 demonstrated AV block (of which 59% had third-degree AV block). Importantly, all patients received dual-chamber devices and randomization was implemented based on programming only. Perhaps because of this, there was a high-degree of crossover in the trial (26%), attributed to the pacemaker syndrome (driven by symptoms of fatigue and dyspnea on exertion). There was no significant difference with respect to incidence of all-cause death, stroke, or HF hospitalization. The primary end point of the study, an assessment of health-related quality of life, reached significance only in patients with SND receiving dual-chamber programming. There was no difference among patients with AV block. Interestingly, incidence of AF was higher in patients with SND assigned to ventricular-only pacing, but not in those with AV block.
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The CTOPP investigators enrolled 2568 patients (with AV block present in 60%) at 32 Canadian centers and randomized them to a “physiologic pacing system” (either atrial-only pacing or dual-chamber) versus a ventricular-only pacemaker. The primary outcome, a composite of cardiovascular death and stroke, was not different the two groups. In subgroup analysis, and in contrast to PASE, there appeared to be greater benefit for physiologic pacing among patients with AV block, although this did not reach significance (P = .29). In addition, rates of crossover resulting from pacemaker syndrome were also considerably lower than PASE, with 99.2% of patients assigned to ventricular-pacing only maintaining that mode. Incidence of AF, however, appeared lower among patients with physiologic pacing (5.3% vs 6.6%, P = .05).
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UKPACE was heralded as the definitive trial to guide mode selection among patients with AV block. In the trial, 2021 patients > 70 years of age undergoing implant for high-grade AV block were randomly assigned to a single-chamber ventricular pacemaker or a dual-chamber pacemaker. Over a median follow-up of 4.6 years, there was no difference in all-cause mortality. There was also no difference with respect to the secondary outcomes of rate of AF, HF, and a composite of stroke, transient ischemic attack (TIA), or other thromboembolism at 3 years. Surprisingly, there was an increase in incidence of AF among patients assigned to dual-chamber pacing in the initial 18 months, which may have reflected a systematic ascertainment bias, as dual-chamber devices could more readily detect AF. Similar to PASE, rate of crossover resulting from pacemaker syndrome at the end of the study was low (3.1%). Interestingly, median percentage of ventricular pacing was higher in patients assigned to dual-chamber pacing (99% vs 94%). There is speculation that—given that AV block may be intermittent—continuous RV pacing may have been unnecessary and diminished the possible benefits of a dual-chamber pacing system. Regardless, it has been these findings that leave open a class I recommendation that ventricular-only pacing is an acceptable alternative in patients with AV block who have specific clinical situations (including but not limited to sedentary patients, those with significant medical comorbidities, or those with vascular access limitations) that make them less likely to benefit from dual-chamber systems (LOE B).11
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There has been a resurgence of interest in ventricular-only pacing because of the development of integrated pulse generator and sensing/pacing systems that are fully self-contained (and are therefore “leadless”). These devices overcome some of the limitations of the conventional transvenous lead-based systems, including the early risk of acute complications such as pneumothorax, upper extremity thrombosis, or frozen shoulder, as well as mitigate longer-term risks such as lead-associated infection, fracture, or need for extraction. Indeed, some of have argued that the lead is the “Achilles’ heel” of a pacing system.24 Two fully integrated pulse generator and sensing/pacing systems have now been studied in human trials: the Nanostim leadless cardiac pacemaker (LCP, St. Jude Medical) and the Micra transcatheter pacing system (TCP, Medtronic) (Figs. 89–5 and 89–6). Both devices rely on a catheter-based deployment tool and are delivered to the RV for ventricular-only pacing.
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The feasibility of LCP was tested in the LEADLESS trial, a prospective, nonrandomized single-arm multicenter study of safety and clinical performance in 33 subjects.25 Indications for implant included permanent AF with slow response or AV block, normal sinus rhythm patients with high-degree block and low level of physical activity or short lifespan, or sinus bradycardia with infrequent pauses or unexplained syncope with abnormal findings at EP study. The overall complication-free rate acutely was 94%,25 with no pacemaker-related adverse events, stable device sensing, and pacing thresholds between 3 and 12 months in follow-up.26 Interim analysis of the LEADLESS II study was also recently reported.27 Similar to LEADLESS, the study was a prospective, nonrandomized, multicenter analysis of 526 patients receiving LCP with a primary outcome of efficacy and safety. Pacemaker implant success was achieved in 95.8% of patients, with an average procedural time of 28.6±17.8 minutes and an average hospital stay of 1.1±1.7 days. Successful implant failure resulted predominantly from inadequately sensed R waves. Serious adverse events were observed in 6.7% over a 6-month period, and included device dislodgement (1.7%), cardiac perforation (1.3%), and vascular complications (1.3%).
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Early results of the Micra TCP trial have also been reported.28,29 A prospective, nonrandomized investigation conducted at 56 centers, criteria for entry were broader than in LEADLESS, including all class I or class II guideline-based indications for pacing. A total of 725 patients underwent implant. The primary indication for enrollment was persistent or permanent atrial tachyarrhythmia (64%), SND (17.5%), and AV block (14.8%). Implant success was achieved in 99.2% and freedom from major complication was 96% at 6 months. Cardiac perforation or effusion (1.6%) and vascular access complication (0.7%) were the most common. No radiographic device dislodgements were noted, but three patients required system revision as a result of elevated pacing threshold, symptoms of pacemaker syndrome, or intermittent loss of capture.
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With relatively short implant times, low rate of dislodgement, and projected longevity lasting 10 to14 years, there is growing enthusiasm with respect to the possible role of fully self-contained CIEDs for pacing. Although they do not expand the indication for pacing, they may be associated with fewer adverse events, particularly those resulting from late infection or extraction, as compared with conventional transvenous systems. Further randomized study will help clarify whether their role is that of niche player or whether they represent a new paradigm in the delivery of care.30
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Implantable Cardioverter-Defibrillators
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Defibrillation to treat VF was first reported in the surgical setting in 1947.31 Less than a decade later, Zoll demonstrated that trans-chest countershock using paddles was a viable means for defibrillation for routine clinical practice.32 Development of an internal, automatic defibrillator was first described and successfully tested by Dr. Mirowski and Dr. Mower in canines by 1970.33 Misgivings regarding the safety profile or appropriate patient population for the device delayed human clinical investigation.34 Indeed, in the initial pilot study, subjects were required to have survived two episodes of cardiac arrest on dual antiarrhythmic therapy in order to enroll.5 Indications for ICDs have expanded since this period of initial work, and can broadly be categorized as (1) applying to patients who have survived prior cardiac arrest, sustained VT/VF, or syncope caused by ventricular arrhythmia (ie, secondary prevention); versus (2) individuals at risk, but who have not yet had a documented episode of sustained VT/VF, arrhythmic syncope, or cardiac arrest (ie, primary prevention).7 A recent HRS/ACC/AHA expert consensus statement also comments on use of ICDs in patients who are not included or not well represented in clinical trials.35 Both sets of secondary and primary prevention recommendations are made with the caveat that patients maintained goal-directed medical therapy and have a reasonable expectation of survival for greater than 1 year with good functional status.
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The fundamental principle guiding ICD therapy in secondary prevention is that patients who have survived sudden cardiac death (SCD) are at increased risk for subsequent events and, therefore, will usually meet the indications for an ICD (Table 89–3). ICD therapy is not recommended in secondary prevention, however, among patients with completely reversible causes for malignant arrhythmia (eg, electrolyte abnormalities, drugs, trauma, or VT amenable to cure with ablation) or those within 48 hours after a diagnosis of MI. Data regarding the 48-hour window of increased risk of VT/VF after MI was initially obtained from early trials of thrombolysis in which ventricular arrhythmia after MI was a marker of increased risk, particularly when occurring greater than 2 days after admission.36,37 The increased mortality attributed to early VT/VF in these studies was incurred during the index hospitalization. In more recent trials of percutaneous coronary intervention (PCI), it was observed that the majority of VT/VF episodes occurred within 48 hours, frequently during or immediately after PCI.38,39,40 Although both early (< 48 hours) and late VT/VF is associated with increased risk, patients with later VT/VF episodes sustained greater mortality in follow-up for both ST-segment elevation MI and non-ST-segment elevation MI populations.
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The indications to implant ICDs for primary prevention among patients with chronic ischemic heart disease (IHD) or nonischemic cardiomyopathy (NICM) are based on large randomized trials that have demonstrated reduction in mortality with ICD therapy. There are also recommendations for ICDs in select clinical situations that have been informed by limited prospective study and consensus opinion. These include inherited arrhythmia syndromes, HCM, arrhythmogenic right ventricular cardiomyopathy (ARVC), nonhospitalized patients awaiting cardiac transplant, sarcoidosis, giant cell myocarditis, and Chagas disease (Table 89–4).
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The primary tool for risk assessment in clinical practice is assessment of left ventricular ejection fraction (LVEF), based on the landmark trials which led to the approval of ICD therapy for SCD prevention. The guidelines acknowledge that the determination of LVEF lacks a “gold standard” and there is variation among commonly used techniques for LVEF assessment (including echocardiography, nuclear study, or cardiac magnetic resonance [CMR]). The writing committee recommended the clinician use the LVEF determination that “they feel is the most clinically accurate and appropriate.”7 In patients who are New York Heart Association (NYHA) class II or III, ICD therapy is indicated for patients with LVEF ≤ 35% resulting from IHD or NICM; for patients who are NYHA functional class I, an LVEF ≤ 30% is recommended for patients with IHD (and may be considered [class IIb] for NICM); among patients with a history of IHD and with inducible VT or VF, the LVEF criterion is relaxed to ≤ 40%, irrespective of etiology of LV systolic dysfunction. The waiting period of 40 days after acute MI or 90 days after revascularization draws in part from large-scale trials assessing efficacy of ICD therapy in these clinical settings and will be discussed further below.
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With regard to special situations, there have been increasing data regarding use of defibrillators among patients with inherited arrhythmia syndromes that have informed specific recommendations for these patients.41 Given that syncope may portend malignant ventricular arrhythmias, there is a class IIa recommendation for primary prevention ICD among long QT syndrome patients who experience recurrent syncopal events while on β-blocker therapy, among patients with Brugada syndrome with a type 1 ECG pattern and arrhythmic syncope, or among lamin A/C mutation-positive patients with progressive cardiac conduction disease (PCCD) with LV dysfunction or nonsustained VT (NSVT). The recommendation is upgraded to class I for catecholaminergic polymorphic VT (CPVT) patients who demonstrate polymorphic VT or bidirectional VT on medical therapy. There are also more modest class IIb indications to consider ICD for patients with Brugada syndrome who develop VF during programmed electrical stimulation, among asymptomatic patients with short QT syndrome and a family history of SCD, among asymptomatic patients with a high-risk early repolarization (ER) pattern or symptomatic family members of ER syndrome patients with inferolateral ER, and in first-degree relatives of patients with idiopathic VF who experience unexplained syncope.
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Specific recommendations have also been elaborated for patients with HCM.10 In this group, there is a class IIa recommendation to proceed with ICD in patients with a family history of SCD in a first-degree relative or with LV wall thickness ≥30 mm or recent unexplained syncope. There is also class IIa recommendation to consider ICD in patients with NSVT and SCD risk factors, including LVOT obstruction (resting gradient ≥ 30 mm Hg), the presence of late gadolinium enhancement (LGE) on CMR, LV apical aneurysm, or malignant genetic mutations. In patients with HCM and only NSVT or abnormal BP response during exercise without SCD risk factors, the recommendation is downgraded to class IIb.
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There have been three pivotal trials that led to the approval of ICDs for secondary prevention: Antiarrhythmics Versus Implantable Defibrillators (AVID),42 the Canada Implantable Defibrillator Study (CIDS),43 and the Cardiac Arrest Survival in Hamburg (CASH) trial.44 AVID was the largest and was conducted first—enrolling 1016 patients who had either survived near-fatal VF or undergone cardioversion for sustained VT with syncope, or with sustained VT and an LVEF of ≤ 40% with symptoms of hemodynamic compromise from VT such as near-syncope, congestive HF, or angina. Patients were assigned to either ICD or antiarrhythmic therapy (amiodarone or sotalol). The trial was stopped early (before its original goal of 1200 patients) because of significance of the primary outcome—overall survival—which was improved in patients randomized to ICDs at 1 year (89.3% vs 82.3%), 2 years (81.6% vs 74.7%), and 3 years (75.4% vs 64.1%) (unadjusted estimates, P< .02). Incidence of tachycardia therapy with either ATP or shocks was common at 3 years (85% for VF patients and 69% for VT patients). Importantly, however, in subgroup analysis, it was found that patients with LVEF > 35% or nonischemic arrhythmia were less likely to benefit from ICD versus antiarrhythmic therapy.
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CIDS and CASH were both smaller than AVID. Eligible patients for CIDS included those who were > 72 hours from MI and electrolyte imbalance and demonstrated documented VF, out-of-hospital arrest requiring defibrillation or cardioversion, sustained VT with syncope, sustained VT with presyncope in patients with LVEF ≤ 35%, or unmonitored syncope with subsequent documentation of spontaneous VT ≥ 10 seconds or sustained VT (≥ 30 seconds) induced at EP study. A total of 659 patients were randomized to either ICD or amiodarone. A nonsignificant 20% relative risk reduction was found in all-cause death and 33% reduction in arrhythmic mortality. Similarly in CASH, 288 patients with resuscitated from cardiac arrest from documented sustained VT or VF were randomized to amiodarone and β-blockade versus ICD, and a 23% nonsignificant reduction in all-cause mortality was noted. Meta-analyses combining the data from AVID, CIDS, and CASH have shown that, when taken together, the benefit of ICDs in secondary prevention does reach significance and is associated with 28% relative risk reduction of overall mortality, driven by a 50% reduction in arrhythmic death.45,46
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Two additional trials bear mentioning with respect to secondary prevention. The first Multicenter Automatic Defibrillator Implantation (MADIT-I) trial evaluated 196 patients with LV systolic dysfunction (LVEF ≤ 35%), prior MI, and either documented asymptomatic NSVT and inducible nonsuppressible sustained VT or VF at EP study.47 Coronary artery bypass grafting (CABG) within the past 2 months or PCI within 3 months were exclusion criteria. Although distinct from secondary prevention in that patients enrolled in MADIT-I had no history of arrhythmic syncope or sustained VT, all patients demonstrated inducible and nonsuppressible (by procainamide or another antiarrhythmic) VT at EP study. These patients were allocated to either ICD or conventional medical therapy, and the trial revealed an impressive reduction in mortality (HR 0.46, P = .009). Also relevant to secondary prevention patients is the Multicenter Unsustained Tachycardia Trial (MUSTT) in which 704 patients with coronary artery disease (> 4 days from the most recent MI or revascularization procedure), LVEF ≤ 40%, and asymptomatic NSVT (lasting for ≥ 3 beats) underwent EP study.48 Patients with sustained VT or VF at EP study were then randomized to either antiarrhythmic therapy with either ICD or EP-guided antiarrhythmic therapy versus no antiarrhythmic therapy. The trial showed that, although patients with EP-guided therapy demonstrated lower risk of arrhythmia, the risk of arrhythmic death was lowered only in patients assigned to receive an ICD (relative risk [RR] 0.24 versus those who received EP-guided antiarrhythmic therapy, P < .001). Perhaps more than any other secondary-prevention trial, MUSTT makes a compelling argument for ICD among patients with coronary artery disease and inducible VT or VF, above and beyond medical therapy.
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Evidence supporting the use of ICDs in the primary prevention of SCD was comprehensively reviewed in a recent report commissioned by the Agency for Healthcare Research and Quality (AHRQ).49 Their meta-analysis of 14 studies showed a significant reduction in all-cause mortality (HR 0.69, 95% CI 0.6-0.79) and an even stronger case for reducing SCD (HR 0.37, 95% CI 0.26-0.52). The seminal trials that led to the approval of ICDs for current indications include MADIT-II,50 the Sudden Cardiac Death-Heart Failure (SCD-HeFT) trial,51 and the Defibrillators in Non-Ischemic Cardiomyopathy Treatment Evaluation (DEFINITE) study.52 In MADIT-II, 1232 patients with prior MI and LVEF ≤ 30% were randomly assigned (in a 3:2 ratio) to ICD or conventional medical therapy. Patients with MI within the past month or coronary revascularization within the prior 3 months were excluded. The trial was stopped early because of the superiority of ICDs. The primary outcome was all-cause death, and was significantly reduced for patients assigned to ICD versus usual care (HR 0.69, P = .016). SCD-HeFT was larger and more inclusive in enrollment than MADIT-II, including NYHA class II or II patients with stable HF and LVEF ≤ 35% from ischemic or nonischemic causes, and randomized subjects to placebo, amiodarone, or single-chamber ICD. The primary outcome was also death from any cause and was significantly reduced for patients assigned to ICD (HR 0.77, P = .007), and was similar for patients with ischemic or nonischemic HF. Finally, DEFINITE enrolled 458 patients exclusively with nonischemic dilated cardiomyopathy, LVEF < 36%, and presence of ambient arrhythmias (NSVT 3 to 15 beats at a rate ≥ 120 bpm) or at least 10 premature ventricular contractions (PVCs) per hour on 24-hour Holter. Patients were randomized to either medical therapy or medical therapy supplemented with single-chamber ICD. The primary end point of all-cause death was better for patients assigned to ICD, but did not reach significance (HR 0.65, P = .08). A secondary end point of reduction in SCD, however, was significantly better for patients assigned to ICD (HR 0.20, P = .006).
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Arguably even more informative than trials demonstrating benefit among primary prevention patients have been three large negative studies which have constrained use in patients after revascularization. These include the Coronary Artery Bypass Graft-Patch (CABG-Patch),53 Defibrillator in Acute Myocardial Infarction Trial (DINAMIT),54 and the Immediate Risk-Stratification Improves Survival (IRIS) study.55 In CABG-Patch, patients scheduled for elective coronary bypass surgery were screened for age < 80 years, LVEF < 36%, and abnormalities on signal-averaged electrocardiogram; 1055 patients were enrolled and finally 900 assigned to either epicardial ICD or control (no ICD). The study was terminated early because of futility (HR 1.07 for all-cause death, P = .64) and was attributed to a perceived low rate of SCD among CABG patients, although this could not be ascertained with certainty because the majority of ICDs used lacked the ability to store electrograms. In addition, postoperative infection was significantly more common among patients assigned to ICD.
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DINAMIT evaluated another high-risk group, patients between 6 and 40 days post MI. A total of 674 patients with LVEF ≤ 35% and evidence of reduced heart-rate variability or elevated average heart rate > 80 bpm on Holter monitoring were randomly assigned to ICD or no-ICD. The primary end point of all-cause mortality was not improved by ICD (HR 1.08, P = .66), whereas the risk of arrhythmic death was significantly reduced (HR 0.42, P = .009). Concerning, however, was that the risk nonarrhythmic death was significantly greater among patients assigned to ICD (HR 1.75, P = .02). Some commentators speculated that inappropriate device therapies might be harmful and have led to this difference.56,57 The larger IRIS trial was meant to tackle the disappointing findings of DINAMIT head-on, enrolling 898 patients 5 to 31 days post MI with LVEF ≤ 40% and either high resting heart rate (≥ 90 bpm) or at least three beats of NSVT at a rate of ≥ 150 bpm. Patients were randomized to ICD or medical therapy alone. Results were in line with what had been found in DINAMIT—overall mortality was not reduced (HR 1.04, P = .78), SCD was reduced in patients assigned to ICD (HR 0.55, P = .049), but nonarrhythmic death was substantially greater for patients assigned to ICD (HR 1.92, P = .001). In part, it was the findings of DINAMIT and IRIS that primed investigators to the possible harm of ICDs, setting the stage for more contemporary trials of device programming to improve outcome (discussed further below).
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Defibrillator systems have evolved from devices requiring an open-chest surgical approach to modern defibrillators that can be placed transvenously. The trials discussed above were conducted exclusively with either an epicardial or transvenous system. Indeed, as noted above in discussion regarding the rationale behind leadless pacing systems, the lead itself may be the weakest link in defibrillation systems—associated with greater risk of periprocedural complication and susceptible to later bacterial seeding and infection, insulations break, or fracture. Although subcutaneous arrays have been utilized to lower defibrillation threshold for a number of years, they have been used in accompaniment with transvenous or epicardial sensing leads for sensing. An entirely subcutaneous system was first conceptualized and demonstrated in canines in 1970,58,59 but the idea largely went unnoticed. It was not until 2001 that the concept was pursued rigorously in human investigation (Fig. 89–7). The first study evaluated 78 patients in whom different configurations of a temporary subcutaneous ICD (S-ICD) were evaluated.60 The best configuration (parasternal electrode and left lateral thoracic pulse generator) was then studied in 49 patients to determine appropriate defibrillation threshold, and then evaluated in longer-term use in a pilot study of 6 patients followed by a nonrandomized trial of 55 patients. Initial results were promising, with the detection and treatment of 12 spontaneous episodes of arrhythmia.
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A number of small cohort studies have now published safety and efficacy data regarding the S-ICD, which has been overall favorable.61,62,63,64,65 The largest data set was pooled from two large registries: the S-ICD System IDE Clinical Investigation (IDE) study and the Boston Scientific Post Market S-ICD Registry (EFFORTLESS) trial, reporting on the results of 882 patients who were followed for close to 2 years.66 Spontaneous VT or VF was detected in 111 discrete events in 59 patients with a first-shock success of 90.1% and 98.2% successful with five available shocks. The 3-year inappropriate shock rate was 13.1% and reduced with dual-zone programming. Device-related complications occurred in 9.6%, with device-related infection requiring revision or removal being the most common. Importantly, given that the device is subcutaneous, no bacteremia or device-related endocarditis occurred, and the complication rate was reduced with operator experience.67 The ongoing Prospective, Randomized Comparison of Subcutaneous and Transvenous Implantable Cardioverter-Defibrillator Therapy (PRAETORIAN; NCT01296022) trial seeks to compare the efficacy and safety of S-ICD versus conventional transvenous ICD systems head-to-head and will help answer questions regarding which type of system to implant for a primary prevention patient going forward.68
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Wearable Cardioverter-Defibrillator
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Use of a wearable cardioverter-defibrillator (WCD) (Fig. 89–8) to terminate VF in humans was first described in 1998,69 and has emerged as a viable option to “bridge” patients during a period of increased risk prior to eventual ICD implantation or to a point at which ICD implantation is no longer indicated. There are limited observational data available regarding the efficacy of WCDs leading to its general approval.70,71 An ongoing study, Vest Prevention of Early Sudden Death Trial/Prediction of ICD Therapies Study (VEST/PREDICTS; NCT01446965) seeks to address the question of whether WCDs in patients with low LVEF (≤ 35%) after MI might benefit from additional protection with randomization to WCDs in addition to goal-directed medical therapy. PREDICTS will follow VEST as part of an ongoing observational study after 2 months (the completion of VEST). The largest real-world data regarding use comes from the WEARIT-II Registry, in which 2000 patients (40% ischemic, 46% nonischemic, and 12% with congenital or inherited arrhythmia) received WCDs for a median duration of 90 days.72 Sustained VT/VF was detected in 2.1% of patients, with therapy delivery required for 1.1% (and the remainder spontaneously terminating). Risk was higher for patients with ischemic cardiomyopathy or congenital/inherited disease than NICM. Similar findings were also seen in another large single-center cohort study.73 The WCD, therefore, may be an option to cover the “gap” highlighted by DINAMIT and IRIS in patients at risk after MI. Importantly, rates of inappropriate therapy were low (0.5%). At the end of WCD use in WEARIT-II, less than half (42%) required ICD, with improvement in LVEF being the most common reason for deferral.
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Cardiac Resynchronization Therapy
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During the past two decades, CRT has emerged as a safe and efficacious device-based therapy for heart failure patients with severe systolic dysfunction and evidence of intraventricular conduction delay. CRT is the use of a pacemaker or defibrillator with three electrical leads to coordinate myocardial contraction. Two leads are endocardial, placed in the right atrium and right ventricle, and a third lead is traditionally placed in a tributary of the coronary sinus overlying the epicardial surface of the left ventricle (Fig. 89–9). CRT exerts its physiological impact via synchronizing ventricular contraction, leading to improved LV filling, reduced mitral regurgitation, increased pumping efficiency, and improved cellular bioenergetics. Indeed, in marked contrast to traditional pacing systems, the goal in CRT is to pace every single beat. Multiple prospective randomized studies have shown that CRT yields long-term clinical benefits, including improved quality of life, increased exercise capacity, reduced heart failure hospitalization, and decreased all-cause mortality. Since the initial development of CRT as a modality, indications for therapy have been tailored to those with evidence of left-sided intraventricular conduction delay, with the strongest indication for patients in sinus rhythm with wide QRS secondary to LBBB (Table 89–5).
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Conventional Indications
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Since its first description in 1994, there has been an explosion of research directed towards elaborating the impact of CRT on ventricular performance, as well as elucidating its clinical impact. A recent comprehensive review commissioned by the AHRQ provides evidence regarding the efficacy and safety of CRT among Medicare beneficiaries.74 Among the first controlled clinical trials of CRT was the Multisite Stimulation in Cardiomyopathy (MUSTIC) trial,75 in which 67 patients with severe heart failure (LVEF ≤ 35% and LV end-diastolic diameter [LVEDD] > 60 mm), sinus rhythm, and QRS interval ≥ 150 ms were implanted with CRT devices. The patients then underwent a single-blind, randomized, crossover study in which the study compared responses during 3-month periods of inactive pacing (or ventricular pacing only at heart rates < 40 bpm) versus aorto-BiV pacing for 3 months. Each patient acted as her or his own control, and the primary end point was 6-minute walking distance (6MWD). This distance was 23% greater with BiV pacing (P < .001); in addition, quality of life score as assessed by the Minnesota questionnaire (P < .001) and peak oxygen uptake were improved and two-thirds fewer hospitalizations occurred for those who received BiV pacing in the first 3 months (P < .05). These results were impressive and led the way for further trials exploring clinical and echocardiographic end points after the CRT.
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Later, two seminal trials led to the initial approval for widespread use of CRT: the Comparison of Medical Therapy, Pacing, and Defibrillation on Heart failure (COMPANION) study76 and the Cardiac Resynchronization-Heart Failure (CARE-HF) study.77 In COMPANION, 1520 patients with NYHA class III or ambulatory class IV HF from ischemic cardiomyopathy or NICM, LVEF ≤ 35%, and QRS ≥ 120 ms, were assigned to optimal pharmacologic therapy (OPT), OPT plus CRT pacemaker (CRT-P), or OPT plus a combined CRT-defibrillator (CRT-D). The primary end point was a composite of time to death or any-cause hospitalization and was significantly reduced by CRT-P (HR 0.81, P = .014) and CRT-D (HR 0.80, P = .01). The secondary end point of all-cause death was reduced by 24% in CRT-P patients in a trend that neared significance (P = .059) and was significant for CRT-D patients (36% reduction, P = .003). The CARE-HF study randomized 813 patients to medical therapy or medical therapy and CRT-P. The primary end point was a composite of death and cardiovascular hospitalization, and was significantly reduced by CRT-P (HR 0.63, P < .001). The secondary end point of mortality alone was also significantly reduced (HR 0.64, P < .002). CRT-P patients demonstrated better quality of life, less severe symptoms of HF, improved LVEF, reduced mitral regurgitation, and reduced N-terminal pro-brain natriuretic peptide (NT-proBNP).
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The Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction (REVERSE),78 the Multi-Center Automatic Defibrillator Implantation Trial-CRT (MADIT-CRT),79 and the Resynchronization-Defibrillation for Ambulatory Heart Failure (RAFT) trials led to an expansion of the indication of CRT to less symptomatic patients.80 Briefly, REVERSE evaluated 610 patients with NYHA class I or II HF with QRS ≥ 120 ms and LVEF ≤ 40%. Patients were randomized to CRT-ON or CRT-OFF. The primary end point was an HF clinical composite, which did not reach significance, but with greater improvement in LV remodeling and significantly reduced time to first HF hospitalization. Overall, the trial was felt to be underpowered. The larger MADIT-CRT study compared CRT-D with ICD only in 1820 patients with QRS ≥ 130 ms, LVEF ≤ 30%, and NYHA class I (ischemic only) or II (ischemic or nonischemic) symptoms. The trial was terminated early because of efficacy (HR 0.66 for primary end point in CRT-D patients, P < .001), driven by a reduction in HF hospitalization. The annual mortality was low, at approximately 3% annually, and was not significantly different in the two groups. Improvement in LV volumes and LVEF was also noted. A few months later, the similarly sized (1798 patients) RAFT study evaluated CRT-D versus ICD in patients with LVEF ≤ 30%, NYHA class II or II HF, and a QRS duration ≥ 120 ms. Results were quite similar, with reduction in the primary end point of all-cause death or HF hospitalization with BiV pacing (HR 0.75, P < .0001). Mortality reduction was also achieved in this slightly more-advanced HF population (HR 0.75, P = .003). Together, MADIT-CRT and RAFT led to a change of the guidelines, with approval for CRT for less symptomatic HF patients and earlier in the pathophysiologic disease process.
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Although initially developed to address the problem of electrical conduction delay (as evidenced by a wide QRS), there was initial enthusiasm that CRT might have a role in patients with narrower QRS and echocardiographic evidence of mechanical dyssychrony. An initial randomized controlled trial, the Cardiac Resynchronization Therapy in Patients with Heart Failure and Narrow QRS (RethinQ),81 showed no difference in a primary end point comparing increase in peak oxygen consumption, although patients with a QRS width of 120 to 130 ms did benefit. The largest and most comprehensive study evaluating the question of CRT in patients with narrow QRS with respect to hard clinical end points was the Echocardiography Guided Cardiac Resynchronization therapy (EchoCRT) trial.82 Eligible patients demonstrated NYHA class III or IV HF, LVEF ≤ 35%, LVEDD ≥ 55 mm, QRS duration ≤ 130 ms, and echocardiographic evidence of LV dyssynchrony (ie, opposing-wall delay of ≥ 80 ms or speckle-tracking anteroseptal-to-posterior wall delay of ≥ 130 ms). Patients were randomized to either CRT-on or CRT-off. The trial was terminated early because of futility, with no benefit found at a mean of 19.4 months. There was also a worrisome signal of increased mortality in CRT-on patients (HR 1.81, P = .02). Persistent or worsened dyssychrony was a marker of worse clinical outcomes.83
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By contrast, the use of CRT in patients with paced QRS complexes (even if the underlying native is narrow) has been shown to be successful at improving outcomes in select populations if pacing percentage is high. Putatively this is because RV pacing is analogous to a LBBB-like activation. The Biventricular versus Right Ventricular Pacing in Heart Failure Patients with Atrioventricular Block (BLOCK HF) trial evaluated whether BiV pacing would be superior to RV pacing in patients with high-degree AV block, NYHA class I to III symptoms, and LVEF ≤ 50%.84 The primary outcome was a composite of time to death for any cause, HF visit requiring intravenous therapy, or increase in LV end-systolic volume index by ≥ 15%. 691 patients were randomized and the primary outcome was reduced significantly (HR 0.74, 95% CI 0.60-0.90), and this effect was also seen when examining clinical end points of time to all-cause death and HF treatment alone (HR 0.73, 95% CI 0.57-0.92). Recent guidelines have taken BLOCK HF into account in consideration for BiV upgrade for patients with chronic RV pacing. The results of the larger Biventricular Pacing for Atrioventricular Block to Prevent Cardiac Desynchronization (BioPace) trial85 looked at a similar population, and preliminary results were presented at the European Society of Cardiology Congress in 2014. In it, any patient with high-degree AV block, or with first-degree block or slow AF with an expected high burden of pacing, could be eligible.86 Patients with normal LVEF and no HF could also enroll, and a total of 1810 patients were randomized. Average ventricular pacing was > 85% in both groups at 1 month and the average LVEF in the study was 55%. Although there was a trend toward benefit for mortality and HF hospitalization reduction, it did not reach significance (HR 0.87, P = .08). Interestingly, there was no significant difference when stratified by LVEF greater or less than 50%. Implant failure was 14.8% among patients assigned to BiV devices and may have also confounded results. Even as fundamental indications expand, implementation of technology continues to be a moving target, particularly with respect to the LV lead in patients with CRT. Further discussion will be provided below to provide a perspective on pacing and defibrillation systems, their fundamental components and implant, as a general background to understanding indications and use.