Europace Advance Access originally published online on August 28, 2007
Europace 2007 9(10):959-998; doi:10.1093/europace/eum189
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GUIDELINES
Guidelines for cardiac pacing and cardiac resynchronization therapy
The Task Force for Cardiac Pacing and Cardiac Resynchronization Therapy of the European Society of Cardiology. Developed in Collaboration with the European Heart Rhythm Association
(Greece); (Switzerland); (France); (France); (Germany); (Belgium); (Italy); (Sweden); (Portugal); (Turkey); (UK); (Poland)
(France); (UK); (Italy); (France); (Norway); (France); (Greece); (The Netherlands); (Denmark); (France); (Germany); (Germany); (Poland); (Czech Republic); (Spain)
(Italy); (Sweden); (Italy); (Spain); (UK); (Spain); (UK); (Spain); (Switzerland); (France); (UK); (Spain); (Italy); (France); (The Netherlands); (Germany)
* Corresponding author: Panos Vardas, Department of Cardiology, Heraklion University Hospital, PO Box 1352 Stavrakia, GR-711 10 Heraklion (Crete), Greece. Tel: +30 2810 392706; fax: +30 2810 542 055; e-mail: cardio{at}med.uoc.gr
Abbreviations: ASSENT-II, Assessment of the Safety and Efficacy of a New Thrombolytic trial • BELIEVE, The Bi vs Left Ventricular Pacing: an International Pilot Evaluation on Heart Failure Patients with Ventricular Arrhythmias multicentre prospective randomized pilot study • CARE-HF, The Cardiac Resynchronization-Heart Failure trial • COMPANION, Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure trial • CTOPP, Canadian Trial of Physiological Pacing • DANPACE, Danish Multicenter Randomized Study on Atrial Inhibited versus Dual-Chamber Pacing in Sick Sinus Syndrome • DAVID, Dual Chamber and VVI Implantable Defibrillator trial • GUSTO-I, Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries-I • GUSTO-III, Global Use of Strategies to Open Occluded Coronary Arteries-III • ISSUE 2, International Study on Syncope of Uncertain Etiology 2 • MILOS, Multicenter Longitudinal Observational Study • MIRACLE, Multicenter InSync Randomized Clinical Evaluation trial • MIRACLE ICD II, Multicenter InSync ICD Randomized Clinical Evaluation trial • MOST, Mode Selection Trial • MUSTIC, Multisite Stimulation in Cardiomyopathy study • OPSITE, Optimal Pacing SITE study • PASE, Pacemaker Selection in the Elderly trial • PATH CHF, Pacing Therapies in Congestive Heart Failure study • PAVE, Left Ventricular-Based Cardiac Stimulation Post AV Nodal Ablation Evaluation • SCD-HeFT, Sudden Cardiac Death in Heart Failure Trial • SYDIT, Syncope Diagnosis and Treatment study • SYNPACE, Vasovagal Syncope and Pacing trial • UKPACE, United Kingdom Pacing and Cardiovascular Events trial • VASIS, The Vasovagal Syncope International Study • VPS, North American Vasovagal Pacemaker Study
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Preamble |
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 Top Preamble Introduction1. Pacing in arrhythmias2. Pacing for specific...3. Cardiac resynchronization...Appendix AAppendix BReferences |
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Guidelines and Expert Consensus Documents summarize and evaluate all currently available evidence on a particular issue with the aim to assist physicians in selecting the best management strategies for a typical patient, suffering from a given condition, taking into account the impact on outcome, as well as the risk–benefit ratio of particular diagnostic or therapeutic means. Guidelines are no substitutes for textbooks. The legal implications of medical guidelines have been discussed previously.
A great number of Guidelines and Expert Consensus Documents have been issued in recent years by the European Society of Cardiology (ESC) as well as by other societies and organizations. Because of the impact on clinical practice, quality criteria for development of guidelines have been established in order to make all decisions transparent to the user. The recommendations for formulating and issuing ESC Guidelines and Expert Consensus Documents can be found on the ESC website (http://www.escardio.org/knowledge/guidelines/rules).
In brief, experts in the field are selected and undertake a comprehensive review of the published evidence for management and/or prevention of a given condition. A critical evaluation of diagnostic and therapeutic procedures is performed including the assessment of the risk/benefit ratio. Estimates of expected health outcomes for larger societies are included, where data exist. The level of evidence and the strength of recommendation of particular treatment options are weighed and graded according to pre-defined scales, as outlined in Tables 1 and 2.
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The experts of the writing panels have provided disclosure statements of all relationships they may have which might be perceived as real or potential sources of conflicts of interest. These disclosure forms are kept on file at the European Heart House, headquarters of the ESC. Any changes in conflict of interest that arise during the writing period must be notified to the ESC. The Task Force report was entirely supported financially by the ESC and was developed without any involvement of the industry.
The ESC Committee for Practice Guidelines (CPG) supervises and coordinates the preparation of new Guidelines and Expert Consensus Documents produced by Task Forces, expert groups, or consensus panels. The Committee is also responsible for the endorsement process of these Guidelines and Expert Consensus Documents or statements. Once the document has been finalized and approved by all the experts involved in the Task Force, it is submitted to outside specialists for review. The document is revised, and finally approved by the CPG and subsequently published.
After publication, dissemination of the message is of paramount importance. Pocket-sized versions and personal digital assistant-downloadable versions are useful at the point of care. Some surveys have shown that the intended end-users are sometimes not aware of the existence of guidelines or simply do not translate them into practice so this is why implementation programmes for new guidelines form an important component of the dissemination of knowledge. Meetings are organized by the ESC and directed towards its member National Societies and key opinion leaders in Europe. Implementation meetings can also be undertaken at national levels, once the guidelines have been endorsed by the ESC member societies, and translated into the national language. Implementation programmes are needed because it has been shown that the outcome of disease may be favourably influenced by the thorough application of clinical recommendations.
Thus, the task of writing Guidelines or Expert Consensus documents covers not only the integration of the most recent research, but also the creation of educational tools and implementation programmes for the recommendations. The loop between clinical research, writing of guidelines, and implementing them into clinical practice can then only be completed, if surveys and registries are performed to verify that real-life daily practice is in keeping with what is recommended in the guidelines. Such surveys and registries also make it possible to evaluate the impact of implementation of the guidelines on patient outcomes. Guidelines and recommendations should help the physicians to make decisions in their daily practice; however, the ultimate judgement regarding the care of an individual patient must be made by the physician in charge of his/her care.
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Introduction |
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TopPreambleIntroduction1. Pacing in arrhythmias2. Pacing for specific...3. Cardiac resynchronization...Appendix AAppendix BReferences |
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Cardiac pacing has been used in the treatment of bradyarrhythmias for more than 50 years and during that time both clinical practice and an impressive body of research have proved its effectiveness objectively, in terms of parameters that includes the patient's quality of life, morbidity, and mortality. There can also be no doubt that the related technology has made great strides over the same period.1
–4 Today, thanks to developments in microelectronics, the devices are smaller, the programming options wider, and the pacing leads thinner but longer lasting than before. All these developments, in both hardware and software, have aimed at the primary goal of appropriate electrical correction of pulse and conduction defects in such a way as to simulate the natural, inherent electrical function of the heart as closely as possible and to satisfy the patient's needs while minimizing side effects. In addition, increased device longevity and the elimination of major and minor complications resulting from treatment have also been the constant aims of both manufacturers and physicians.
During the last 12 years, electrical stimulation has advanced further, into the realm of ventricular resynchronization as an adjunctive therapy for patients with drug-refractory heart failure and ventricular conduction delay. It must be remembered that cardiac pacing for both bradyarrhythmia and cardiac resynchronization therapy (CRT) was first used clinically in Europe.4,5,264,265
The guidelines for the appropriate use of pacemaker devices presented in this document, a joint European Society of Cardiology (ESC) and EHRA initiative, aim to provide for the first time in Europe an up-to-date specialists’ view of the field. The guidelines cover two main areas: the first includes permanent pacing in bradyarrhythmias, syncope, and other specific conditions, whereas the second refers to ventricular resynchronization as an adjunct therapy in patients with heart failure.
Pacing in bradyarrhythmia, syncope, and other specific conditions
The recommendations for pacing in bradyarrhythmias were based on an extensive review of the literature, old and new, with a view to reaching evidence-based conclusions. Where the literature is lacking, mainly with regard to conditions where no other therapy could replace pacing, the recommendations are based on expert consensus. The guidelines that follow concern patients who have permanent and irreversible disturbances of the systems for generation and conduction of the cardiac stimulus. The text will often make reference to the fact that the decision to implant a device depends on the accurate judgement of the treating physician, who must determine whether the damage is of a permanent and irreversible nature.
When the pathophysiology of the condition is judged to be fully reversible, for example, in the case of drug effects (digitalis intoxication) or electrolyte disturbances, or most likely reversible, such as in inflammatory or ischaemic myocardial disease, the bradyarrhythmic condition should be treated initially without permanent implantable device therapy. Of course, in daily practice, the nature of the disturbances of stimulus production and conduction is often ambiguous and the permanence of the condition is unclear.
As mentioned above, the focus of these guidelines is the appropriate use of pacemakers in patients with bradyarrhythmias. Obviously, the work of the committee would be incomplete if it limited itself only to recommendations concerning indications for pacing and failed to include consideration of the proper pacing mode in each case. It was therefore considered essential to cover in this report the proposed pacing modes for each condition.
On the other hand, the committee decided that the document should not include recommendations for the choice of pacing leads or for their extraction or replacement. These subjects will be covered by forthcoming EHRA documents.
Cardiac resynchronization therapy
Cardiac pacing as an adjunct therapy for heart failure began to be the subject of scientific research at the start of the 1990s. The first pacing modality to be examined was dual-chamber pacing with a short atrioventricular (AV) delay, in patients with heart failure but without the classical bradyarrhythmic indications for pacing. The first studies in this area gave promising results. Acute and short-term improvements resulted from the optimization of left ventricular (LV) filling and a reduction in pre-systolic mitral regurgitation. Unfortunately, the initial results were not confirmed by subsequent studies and the early hopes raised by dual-chamber pacing with a short AV delay for heart failure patients were not fulfilled.
In contrast, atrio-biventricular pacing for patients with symptomatic heart failure and intra- or interventricular conduction disturbances has proved beneficial. During the last decade, a number of studies have established a theoretical basis for this new therapy and have drawn related conclusions regarding the importance of resynchronization in terms of improving symptoms, morbidity, and mortality in these patients.
This document presents the recommendations of the committee concerning indications for CRT based on the most recent studies.
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1. Pacing in arrhythmias |
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TopPreambleIntroduction1. Pacing in arrhythmias2. Pacing for specific...3. Cardiac resynchronization...Appendix AAppendix BReferences |
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1.1. Sinus node disease
Sinus node disease, also known as sick sinus syndrome, designates a spectrum of sinoatrial dysfunction that ranges from the usually benign sinus bradycardia to sinus arrest or to the so-called bradycardia–tachycardia syndrome.6
The latter is characterized by the development of paroxysmal atrial tachyarrhythmias in patients with sinus bradycardia or sinoatrial block. Some patients with frequent, repetitive, long-lasting episodes, or atrial fibrillation (AF) may remodel their atrial myocardium, including the sinoatrial region, and are prone to systemic embolism.7 In patients with sinus arrest, there may be an ectopic atrial or AV junctional escape rhythm. Some patients with sustained AF or flutter may have an underlying sinus node dysfunction that becomes patent after cardioversion of the atrial tachyarrhythmia. An additional manifestation of sinus node dysfunction is the lack of an adequate chronotropic response to exercise. Sinus node disease, as a clinical entity, encompasses not only disorders of the sinus node impulse formation or its conduction to the right atrium, but also a more widespread atrial abnormality that is the substrate for the development of atrial tachyarrhythmias. In addition, some patients with signs of sinus node dysfunction may also present AV conduction abnormalities.
We lack adequately controlled pathological studies to define the structural basis of the sick sinus syndrome and its various clinical and electrocardiographic manifestations. Future studies must compare the structural changes in the sinoatrial region of patients with various forms of sinus node disease, who otherwise have normal hearts, with appropriate controls matched for age and gender. To attribute specific pathological meaning to structural findings observed in anecdotal necropsy reports on patients with sick sinus syndrome is openly speculative. To conduct pathological studies on the sinus node region is not a simple task because of the complexity of this area.8 The sinus node tissue is widely distributed at the junction between the superior vena cava and the right atrium, which probably implies that for the development of significant sinus node disease, an ample atrial architectural disorder is needed.
The most dramatic symptom of the disease is syncope or near syncope, due to sinus arrest or sinoatrial block, which may often be reflex in nature.9
Sinus pauses may sometimes be followed by atrial tachyarrhythmias that are sufficiently rapid to prolong the hypotension, causing syncope or dizziness. Apart from the above, it is not uncommon for the symptoms of the disease to be limited to fatigue or dyspnoea, reduced exercise capacity, and cognitive impairment, as a consequence of exaggerated bradycardia (<40 b.p.m.) and chronotropic incompetence.10,11 The latter is characterized by an impaired heart rate response to exercise and is generally defined as failure to achieve 85% of the age-predicted maximum heart rate.10,11
The diagnosis of sinus node disease is based on relating a variety of electrocardiographic findings with the symptoms. In some patients with syncope of undetermined origin, the underlying mechanism is a symptomatic paroxysmal sinus node dysfunction that cannot be easily demonstrated by conventional 24 or 48 h Holter monitoring. In such patients, an implantable loop recorder may be the only way of establishing the correct diagnosis. We should also take into consideration the interaction between sick sinus syndrome and neurally mediated syncope. Apart from syncope caused by prolonged pause following the termination of tachycardia in the brady–tachy syndrome, the vast majority of the other syncopes are due to, or favoured by, an abnormal reflex. Moreover, if a persistent bradycardia clearly defines sick sinus syndrome, the meaning of intermittent bradycardia and sinus arrest is less clear. Indeed, the same event (i.e. intermittent sinus arrest) may be diagnosed by one physician as intermittent sick sinus syndrome and by another as cardioinhibitory neurally mediated syndrome. In general, the same syncope is diagnosed as neurally mediated if not documented, whereas if there is the fortuitous documentation of a pause, it is diagnosed as sick sinus syndrome.
Electrophysiological evaluation of sinus node function includes the measurement of the corrected sinus node recovery time and the sinus node conduction time. It is beyond the scope of these guidelines to review the sensitivity, specificity, and diagnostic accuracy of the various cut-off points that have been advanced during the last 25 years for these two sets of parameters.
1.1.1. Indications for pacing in sinus node disease
Once sinus node disease, mild or severe, is diagnosed, the question arises whether to implement permanent pacing or not. Long experience, together with a number of studies, has shown that pacing in sinus node disease contributes more to relieving symptoms and reducing the episodes of AF12–16 than to reducing mortality in these patients.17–19
The indications for pacing in sinus node disease, on the strength of evidence in the available older and modern literature, are given in Table 1.1.1. It is important to note here that when sinus node disease is diagnosed, atrial tachyarrhythmias are likely, even if not recorded, so that apart from pacing serious consideration should be given to oral anticoagulation therapy if not contraindicated.20
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1.1.2. Choice of the pacing mode for patients with sinus node disease
During the last two decades, several clinical endpoint trials, as well as developments in pacing devices, have increased our knowledge and expanded the possibilities for optimal pacing therapy in patients with symptomatic sinus node disease. The principal endpoints of those trials, comparing atrial with ventricular based pacing, were mortality, AF, frequency of thrombo-embolic episodes and stroke, heart failure, pacemaker syndrome, and the patients’ quality of life.
The first randomized trial to address these matters was by Andersen et al.21 They studied 225 patients with sinus node disease and intact AV conduction, who were assigned randomly to either atrial or ventricular pacing. At the end of a 5.5-year period, the patients who were paced in AAI mode had significantly lower incidences of AF, thrombo-embolic events, heart failure, cardiovascular mortality, and total mortality, compared with those paced in VVI mode. Two things were unique about that study: it was the only randomized study to date that compared pure AAI and VVI modes over a long follow-up period and it was also the only one to show a clear benefit in terms of all the clinical parameters examined, and primarily in mortality, for patients who had atrial pacing.
The following studies examined the role of VVI compared with DDD mode in this patient population. Lamas et al.,22 in the PAcemaker Selection in the Elderly (PASE) trial, studied 407 patients who were paced for a variety of indications, including 175 who suffered from sinus node dysfunction. All patients received a dual chamber, rate adaptive system, which was randomly programmed to either VVIR or DDDR mode, and were studied prospectively for 2.5 years. The results showed no statistically significant difference between the two modes of pacing as regards the incidence of thrombo-embolic episodes, stroke, AF, or the patients’ quality of life, for the patient population as a whole. There was a non-significant trend favouring atrial-based pacing in the subgroup with sinus node disease. However, the short follow-up of the study, the very large crossover from VVIR to DDDR and the problem of intention to treat analysis must be taken into consideration.
The Canadian Trial of Physiological Pacing (CTOPP),23 a prospective, randomized study, compared the clinical outcomes in 2568 patients who were randomized to atrial based or ventricular pacing for a mean follow-up period of 3.5 years. The study found no significant difference between the two treatment groups in the combined incidence of stroke or death or in the likelihood of hospitalization for heart failure. However, after 2 years of follow-up, physiological pacing was associated with an 18% relative reduction in the development of chronic AF. A subgroup of patients who were paced for sinus node dysfunction showed no trend towards a benefit from atrial-based pacing in terms of mortality or stroke.
Finally, the Mode Selection Trial (MOST)24 in sinus node dysfunction studied prospectively 2010 patients who were randomized to either DDDR or VVIR mode and were followed for a mean period of 2.7 years. There were no statistically significant differences between the groups in the incidence of death or stroke, but there was a 21% lower risk of AF, a 27% lower risk of hospitalization for heart failure and a better quality of life in the DDDR group, compared with those paced in VVIR mode. Importantly, the study also showed that of the patients initially randomized to VVIR pacing, 37.7% were later switched to DDDR, most usually because of pacemaker syndrome.
The occurrence of bradycardia-dependent and other atrial tachyarrhythmias may cause symptoms and may, therefore, lead to consideration of pacing. In the case of bradycardia-dependent atrial tachyarrhythmias, which are typical of sinus node disease, pacing has been proven to be effective in their prevention. This was seen in the first Danish trial21 and reinforced by the results of CTOPP,23 MOST,24 and the DANPACE pilot study.25 When atrial arrhythmias are not suppressed simply by raising the atrial rate both at rest and, if necessary, on effort, recent pacemaker designs offer a host of atrial antitachycardia preventive and therapeutical pacing algorithms that have been shown to have benefit in some patients. However, the available clinical trials26–31 have not proven their efficacy in the sinus node disease population. The picture may be complicated by the use of Class I antiarrhythmic drugs or amiodarone, which may not only affect sinus node automaticity but also depress atrial conduction, the latter resulting in potential pro-arrhythmic effects.
Summarizing the results of the above prospective, randomized studies, as well as two review papers,32,33 we can conclude that in patients with sinus node disease the incidence of AF is lower in those who are given atrial or dual-chamber pacemakers than in those treated with ventricular pacing alone. Moreover, in the Cochrane review, which included five parallel and 26 crossover randomized controlled trials, there was a statistically significant trend towards dual-chamber pacing being more favourable in terms of exercise capacity and pacemaker syndrome.34
However, as far as stroke, heart failure and mortality are concerned, the findings are conflicting and we cannot draw significant conclusions regarding atrial based vs. ventricular pacing.
Selection of pacing for sinus node disease must always depend on symptoms, although these have broadened from only syncope and dizziness to include malaise, some of which is drug induced, and palpitations. Selection of pacing mode and device is more complex, but the trend is towards dual-chamber pacing with minimization of right ventricular stimulation (in order to avoid changes leading to desynchronization of the ventricles as a result of their being depolarized from the right ventricular apex), rate modulation (RR), and a panoply of antitachycardia algorithms possibly combined with stimulation of the atria from the septum rather than the appendage (Figure 1). However, no consistent data from large randomized trials support the use of alternative single-site atrial pacing, multisite right atrial pacing, or biatrial pacing in sinus node disease patients. Ventricular pacing alone can no longer be recommended, and furthermore, dual-chamber pacing increases quality-adjusted life expectancy at a cost that is generally considered acceptable.34 Regarding the choice of AAI or DDD pacemaker implantation, we should take into consideration that although DDD is more expensive, there is a possibility, albeit small (
1% of annual incidence), of the future development of AV block.35,36
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1.2. Atrioventricular and intraventricular conduction disturbances
In AV block, atrial activation is conducted to the ventricles with a delay, or is not conducted at all, during a period when the AV conduction pathway (AV node or His-Purkinje system) is not expected to be refractory. Traditionally, on the basis of the electrocardiographic criteria, AV block is classified as first, second, or third degree, and depending on the anatomical point at which the conduction of the activation wavefront is impaired, it is described as supra-Hisian, intra-Hisian, or infra-Hisian.
In the first-degree AV block, every atrial stimulus is conducted to the ventricles, but the PR interval is prolonged to >200 ms. The conduction delay may occur at the level of the AV node or at the His-Purkinje system. If the QRS complex is narrow, the conduction delay is usually in the AV node and rarely within the His bundle. If the QRS is wide, the conduction delay may be either in the AV node or in the His-Purkinje system and only a His bundle electrogram can locate it precisely.
A second-degree AV block is characterized by the fact that one or more atrial stimuli are not conducted to the ventricles. It is divided into type I, or Wenckebach, or Mobitz I, and type II, or Mobitz II AV block. In type I, the electrocardiogram (ECG) shows a progressively increasing PR interval until an atrial stimulus fails to be conducted to the ventricles. Often, the increase in the PR interval is subtle in the last cardiac cycles before the blocked P wave and can only be recognized in comparison with the shortest PR interval, which usually follows the blocked P wave. The delay is usually in the AV node and deterioration to a higher degree of AV block is uncommon. However, in cases with a wide QRS complex, an electrophysiological study is required to determine the level of the block. In type II AV block, provided there is normal sinus rhythm, the PR interval is constant before and after the blocked P wave. In this type, the conduction block is usually in the His-Purkinje system, especially in the case of a wide QRS.
In complete (third-degree) AV block, no atrial stimulus is conducted to the ventricles and the ventricles are depolarized by an escape rhythm. Although the escape rate may have significance for the development of symptoms, the site of escape rate origin is of major importance for patients’ safety (i.e. in the AV node, intra- or infra-Hisian).
AV block was the first indication for pacing, and today, it remains one of the most common reasons for pacemaker implantation. Nevertheless, because of the lack of large, comparative, randomized studies, there are still open questions about the indications for pacing, others that concern the pacing mode, and numerous issues regarding the lead implantation site. The decision to implant a pacemaker is based, to a large extent, on the presence of symptoms that are directly related to the bradycardia caused by the AV block. The situation may become even more complex when the conduction disturbance is intermittent. In such a case, the information provided by the surface ECG is limited and a 24 h Holter ECG recording, or even longer rhythm recordings using an external or implantable loop recorder, may be required.
1.2.1. Indications for pacing
In the case of complete AV block, there are a number of non-randomized studies showing that permanent cardiac pacing improves survival, especially in patients who experience episodes of syncope.37–42 In type I second-degree AV block, the indications for permanent pacing are controversial, unless the conduction delay occurs below the AV node or there are symptoms.43,44 However, some authors suggest that pacemaker implantation should be considered even in the absence of symptomatic bradycardia or organic heart disease, because survival is significantly better for paced than for unpaced asymptomatic elderly patients, especially when type I second-degree AV block occurs during diurnal hours.45
In type II second-degree block, especially when there is also a wide QRS, progression to complete heart block and the appearance of symptoms are common;43,46,47 thus pacing is recommended. In patients with first-degree AV block, cardiac pacing is not recommended unless the PR interval fails to adapt to heart rate during exercise and is long enough (usually >300 ms) to cause symptoms because of inadequate LV filling, or an increase in wedge pressure, as the left atrial systole occurs close to or simultaneous with the previous LV systole. In such cases small, uncontrolled studies have shown an improvement in patients’ symptoms.48,49
It should be noted that before the decision for permanent pacing is made, it should be checked whether the AV block is due to a reversible cause, such as acute myocardial infarction, electrolytic disturbances, drugs that can be discontinued (digoxin, non-dihydropyridine calcium channel blockers, beta-blockers, and so on), sleep apnoea, peri-operative hypothermia, or inflammation or vagotonia arising from factors that can be avoided.
1.2.2. Acquired atrioventricular block in special cases
Distal AV block may be observed during effort and, if not due to ischaemia, it is probably caused by damage to the His-Purkinje system and has a poor prognosis.50,51 In this case, permanent pacing is recommended, as it is also in patients who suffer from a progressively deteriorating condition such as amyloidosis, sarcoidosis, or neuromuscular diseases.52–58 Pacing is also recommended in patients developing permanent AV block as a complication of a catheter ablation procedure, although there are no controlled studies regarding this.59,60 It is also recommended in patients developing AV block after heart valve surgery, because its progression is unpredictable (Table 1.2.1).61 Congenital AV block, or AV block after myocardial infarction, and AV block due to enhanced vagal tone are discussed in separate sections.
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1.2.3. Pacing for chronic bifascicular and trifascicular block
The term ‘bifascicular block’ refers to an electrocardiographic picture of complete right bundle branch block with anterior or posterior left hemiblock or of complete left bundle branch block alone. The term ‘trifascicular’ block means impaired conduction in all three branches at the same time, or at different times, although it has also been used to describe bifascicular block together with first-degree AV block. The term ‘alternating bundle branch block’ refers to electrocardiographically demonstrated block of all three branches on the same or successive ECG recordings. The prevalence of bundle branch block has been found to increase with age and is estimated at
1% of the population aged >35,62,63 whereas it is higher at 17% at age 80 years.64 In addition, we know that patients with bundle branch blocks often have other cardiac diseases, mainly coronary artery disease and hypertensive heart disease, which explains their higher mortality rate (2–14%).65–68 Syncope is usually seen in patients with delayed conduction in the bundles of the left and right branches, although the risk of progression to high-degree AV block varies. The annual incidence of progression to high-degree AV block in unselected patients is estimated to be 1–4%,65,68–71 although syncope has been found to be the sole predictive factor. The annual incidence of progression is 5–11% in syncopal patients, but just 0.6–0.8% in patients without syncope.66,72
1.2.4. Indications for pacing
In patients without syncope, the rate of progression to high-degree AV block is low and there is no non-invasive technique with a high predictive value. The results of studies that employed an electrophysiological study have shown that the finding of an HV interval >100 ms, or the demonstration of intra- or infra-Hisian block during incremental atrial pacing at a pacing rate <150 b.p.m., is highly predictive for the development of high-grade AV block, but the prevalence of these findings is very low, and thus their sensitivity is low.71,73–75 Thus, in asymptomatic patients with bifascicular or trifascicular block, permanent pacing is considered appropriate only in those who exhibit intermittent second- or third-degree AV block, or signs of a severe conduction disturbance below the level of the AV node (HV >100 ms, or intra- or infra-Hisian block during rapid atrial pacing) during an electrophysiological study carried out for a different reason. It is unknown whether, apart from preventing future symptoms, pacing improves survival in these patients; however, to date, pacemaker treatment has been found to have no beneficial effect on survival.66,71,76
In patients with syncope and bundle branch block, the demonstration of definite abnormalities of the His-Purkinje conduction predicts the development of stable AV block in some 87% of patients.77–79 These patients should undergo pacemaker implantation (Class I, level of evidence C). In patients with bundle branch block and a normal electrophysiological study, the use of an implantable loop recorder has shown that most syncopal recurrences are due to prolonged asystolic pauses, mainly attributable to sudden-onset paroxysmal AV block.80 Because of the high, short-term incidence of AV block in patients with syncope and bundle branch block who have a normal HV conduction time, an acceptable strategy could be to implant a pacemaker rather than a loop recorder (Class IIa, level of evidence C). An electrophysiological study is considered normal in the absence of one of the following: (i) abnormal sinus node recovery time; (ii) baseline HV interval 
70 ms; (iii) second- or third-degree His-Purkinje block demonstrated during incremental atrial pacing, or high-degree His-Purkinje block elicited by intravenous administration of ajmaline; (iv) induction of sustained monomorphic ventricular tachycardia with programmed electrical stimulation; (v) induction of rapid, haemodynamically unstable, supraventricular tachycardia, particularly if the spontaneous symptoms are reproduced.
Finally, it should be noted that in patients with neuromuscular disease and any degree of fascicular block, with or without symptoms, cardiac pacing may have a place, in view of the unpredictable progression of AV conduction disease.52–58
Pacemaker mode selection in chronic bifascicular and trifascicular block is summarized in Figure 2 (see also Table 1.2.2).
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1.2.5. Choice of pacing mode for patients with atrioventricular block
In patients with AV block, pacing and sensing of the ventricles are essential. Suitable pacing modes are VVI and DDD or alternatively single-lead VDD (Figure 2). Recent prospective, randomized studies of patients in sinus rhythm compared ventricular with AV pacing, having endpoints such as mortality, quality of life, and the occurrence of AF, stroke, or thrombo-embolic episodes. In the CTOPP study, where 60% of the patients had AV block, the primary endpoint, the occurrence of either stroke, or death from cardiovascular cause did not differ significantly between VVI and DDD.81
,82 Nor was there any difference in the annual rates of death from all causes, of stroke, or of hospitalization for congestive heart failure (CHF). The only significant difference found was in the annual incidence of AF. A subgroup analysis carried out as part of the same study found a trend for younger patients (<74 years) to benefit from physiological pacing, in terms of the risk of stroke or death from cardiovascular causes. Nonetheless, it should be noted that a later analysis of the CTOPP study found that pacemaker-dependent patients gained a significant benefit from DDD pacing when compared with VVI, as regards cardiovascular death or stroke, cardiovascular death, and total mortality.83 Another prospective, randomized study (PASE) found no difference in quality of life, cardiovascular events, or death between patients with AV block, who were paced in DDD or VVI mode.84 Similar results were noted in the UKPACE study in elderly patients, in whom the rate of death from all causes or the incidence of cardiovascular events was not affected by the pacing mode.85 These studies found that a high percentage, ranging from 5 to 26% of these patients, developed pacemaker syndrome when paced in the VVI mode. Regarding the use of single-lead VDD pacing in cases with normal sinus node function, recent studies have shown that it is equivalent to DDD pacing, reducing the implantation and follow-up costs.86–89
Patients with AV block or bundle branch block and an indication for permanent pacing are of special concern if their LV ejection fraction (LVEF) is depressed (
35%). The DAVID trial has shown that, in patients requiring an implantable cardioverter defibrillator (ICD) without an indication for permanent pacing, DDDR stimulation at 70 b.p.m. is worse than VVI backup pacing at 40 b.p.m. in terms of a combined endpoint including mortality and worsening of heart failure.90 In this patient population, the physician should take into consideration several important points, such as whether the patient is a candidate for conventional pacing or an ICD and/or a biventricular device for cardiac resynchronization. In addition, small studies have shown that upgrading AV pacing systems to biventricular systems improves LV systolic function,91,92 whereas in a recent study, it was found that in patients with LV dysfunction who need permanent pacing for conventional indications, biventricular stimulation is superior to right ventricular pacing with regard to LV function, quality of life, and maximal as well as submaximal exercise capacity.93 These matters will be further discussed in detail in the cardiac resynchronization section.
A further issue that must be addressed is the choice of pacing site or combination of sites in the right ventricle. What is clear so far is that the right ventricular apex, although easily accessible and ideal for electrode stability with low sensing and pacing thresholds, does not achieve the best possible haemodynamic result,94 while in the long-term it may have an adverse effect on LV function and lead to structural remodelling as well as disturbances of LV perfusion and innervation.95–101 However, conflicting results have emerged from studies that investigated the acute and chronic effects of alternative pacing sites, such as the right ventricular outflow tract or the combination of outflow tract and apex, compared with pacing from the apex alone. Acute haemodynamic studies generally found that outflow tract or dual-site pacing was superior, whereas most of the controlled studies with permanent pacing found it to be equivalent to right ventricular apical pacing.100,102–111 Septal pacing could be more valuable, as two small controlled studies have recently shown that it preserved LV function better in the mid-to-long term when compared with apical pacing.100,114 His-bundle pacing or para-Hisian pacing could be also of interest for patients with narrow QRS. It appears both feasible and safe, compared with conventional right apical pacing, and may allow an improvement in functional and haemodynamic parameters over long-term follow-up.112 In such patients, biventricular stimulation is superior to right ventricular apical pacing in terms of contractile function and LV filling.113 However, no recommendation can be proposed concerning the location of the right ventricular pacing site.
Pacemaker mode selection in acquired AV block is summarized in Figure 2.
1.3. Recent myocardial infarction
1.3.1. Pacing in conduction disturbances related to acute myocardial infarction
The major conduction abnormalities associated with acute myocardial infarction include AV block and intraventricular conduction disturbances.115–118 They are the result of both autonomic imbalance and ischaemia or necrosis of the conduction structure.
Despite the development of new methods for the management of acute myocardial infarction (including thrombolysis and percutaneous coronary intervention), the incidence of intraventricular conduction disturbances has not changed significantly, whereas the incidence of AV block has decreased but remains still high.115,116,119–122
Data from 75 993 patients enrolled in four large, randomized, clinical trials (GUSTO-I, GUSTO-IIb, GUSTO-III, and ASSENT-II) suggest that AV block occurs in almost 7% of cases of acute myocardial infarction.119 Patients with peri-infarction AV block have higher in-hospital and late mortality than do those with preserved AV conduction.119
Similarly, data regarding the incidence of intraventricular conduction abnormalities in patients with an acute myocardial infarction treated with thrombolytic agents suggest that the incidence of bundle branch block has not been altered significantly by thrombolytic therapy, occurring in a transient form in up to 18.4% of patients and in a persistent form in up to 5.3%.122
Conduction disturbances carry a poor prognosis, with a significant increase in the mortality rate even in the thrombolytic era.115–122 The increase in mortality risk is largely seen within the first 30 days in the setting of both an inferior and an anterior myocardial infarction. However, when AV or intraventricular conduction block complicates acute myocardial infarction, the long-term prognosis for survivors is related primarily to the extent of myocardial injury, the degree of heart failure, and the higher incidence of haemodynamic complications.115–123
The location of the infarct influences the type of conduction disturbances in the setting of an acute myocardial infarction. AV block associated with inferior wall infarction is located above the His bundle in the vast majority of patients, whereas AV block associated with anterior wall myocardial infarction is more often located below the AV node.124 Thus, the former is usually associated with transient bradycardia, with a narrow QRS escape rhythm above 40 b.p.m. and low mortality, whereas the latter is associated with an unstable, wide QRS escape rhythm and extremely high mortality (up to 80%) due to the extensive myocardial necrosis. Intraventricular conduction disturbances are more commonly developed in the setting of an anterior-anteroseptal infarction as a result of specific blood supply conditions.118,124 Their presence during an acute myocardial infarction is associated with an unfavourable short- and long-term prognosis and an increased risk of sudden cardiac death (SCD).
The nature and prognosis of conduction disturbances following an acute myocardial infarction are somewhat distinct from other forms of conduction abnormalities. Moreover, indications for permanent pacing after acute myocardial infarction are related to the coexistence of AV block and intraventricular conduction defects.40,125,126 We must keep in mind that in patients with an inferior wall infarction conduction abnormalities may be transient (resolution within 7 days) and are often well tolerated.127,128 Therefore, in such circumstances, there is generally no need for pacemaker implantation. Recommendations for cardiac pacing in persistent conduction disturbances (more than 14 days) related to acute myocardial infarction are summarized in Table 1.3.1.
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In the context of thrombolysis and revascularization, data on persistence of conduction abnormalities and prognosis are lacking. Arbitrary definitions of transience and persistence have been proposed. Mobitz II with bundle branch block and third-degree AV block with wide QRS in post-myocardial infarction patients are considered to have a similarly poor prognosis.
1.4. Reflex syncope
Reflex syncope includes a wide spectrum of different entities that share common mechanisms (vasodilation and/or bradycardia). It is considered to be the consequence of a reflex that, when triggered, induces an acute, inappropriate response mediated by the autonomic nervous system. The main causes of reflex syncope are shown in Table 1.4.1. In this pathology syncope is the only symptom that may justify pacemaker implantation. This excludes dizziness, light-headedness and vertigo, which are beyond the scope of pacing therapy even in patients with an abnormal response to tests considered to be diagnostic of reflex syncope. Syncope should be diagnosed according to the definition in the syncope guidelines published by the ESC,129 as follows: ‘Syncope is a symptom, defined as a transient, self-limited loss of consciousness, usually leading to falling. The onset is relatively rapid, and the subsequent recovery is spontaneous, complete, and usually prompt. The underlying mechanism is transient global cerebral hypoperfusion’.
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Although some patients with orthostatic hypotension or situational syncope have been treated by implantation of a permanent pacemaker, the series is too limited and the results too contradictory130
–133 to warrant separate consideration in the present guidelines. These autonomic diseases, which cause syncope mainly via major hypotension and/or bradycardia, are not presently a recognized indication for pacing, even though some individuals might benefit.130,134 This discussion will be restricted to the role of pacing in patients with carotid and vasovagal syndromes, with a mention of adenosine sensitive syncope.
1.4.1. Carotid sinus syndrome
It has long been observed that pressure at the site where the common carotid artery bifurcates produces a reflex that leads to a slowing of heart rate and a fall in blood pressure (BP). Some patients with syncope exhibit an abnormal response to carotid massage.135,136 A ventricular pause lasting 3 s or more and a fall in systolic BP of 50 mmHg or more is considered abnormal and define carotid sinus hypersensitivity.137–139 Carotid sinus massage is a tool used to demonstrate carotid sinus syndrome in patients with syncope; its precise methodology and results are reported in the guidelines for syncope.129 It should be emphasized that the reproduction of symptoms during the massage is necessary to diagnose carotid sinus syndrome, whereas without this the diagnosis is carotid hypersensitivity.140 Although carotid sinus syndrome is recognized as a potential cause of spontaneous syncope, it is still under investigation in the current clinical practice and is therefore probably underestimated.
1.4.1.1. Indications for pacing in carotid sinus syndrome
The first reports of the abolition of syncope in carotid sinus syndrome by permanent pacing appeared in the 1970s.141,142 Subsequent investigations,143,144 including non-randomized comparative studies,145 showed that pacing in such patients could significantly reduce the number of syncopal episodes, and in the mid-1980s, pacing became the approved treatment. The first randomized trial comparing pacing and no pacing was reported in the 1990s.146 This study included 60 patients: 32 were included in the pacemaker arm (18 patients with VVI and 14 patients with DDD pacemaker) and 28 in the ‘no treatment’ group. After a mean follow-up of 36 ± 10 months, syncope recurred in 9% of the pacemaker group, compared with 57% in the untreated patients (P < 0.0002). In another study, patients with a cardioinhibitory response to carotid sinus massage received a pacemaker that was designed to record asystolic episodes. Long pauses (>6 s) were detected in 53% of the patients during 2 years follow-up, suggesting that a positive response to carotid massage predicts the occurrence of spontaneous long ventricular pauses147 and that pacing therapy is able to prevent the symptoms of these long pauses. Since drug therapy for cardioinhibitory carotid sinus syndrome has been abandoned,148 cardiac pacing appears to be the sole beneficial treatment for these patients,143–146 in spite of there being only one positive randomized trial with a relatively small number of patients.147 Recommendations for cardiac pacing in carotid sinus syndrome are summarized in Table 1.4.2.
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1.4.1.2. Choice of the pacing mode in carotid sinus syndrome
Although it has been argued that single-chamber ventricular pacing may be sufficient in those relatively infrequent cases where there is neither a marked vasodepressor component to the reflex nor a so-called ‘ventricular pacing effect’,149
when pacing is prescribed dual-chamber cardiac pacing is preferred.144,150 Some dual-chamber pacemakers with sophisticated algorithms were specially designed to limit the effects of hypotension consequent to vasodilation. The algorithms were based on acceleration of the pacing rate when intrinsic heart rate suddenly decreases. Although acute results were in favour of these algorithms,151 there is no well-designed trial demonstrating that they are superior to simple rate hysteresis during long-term pacing.
1.4.2. Vasovagal syncope
Vasovagal syncope accounts for 50% of all the cases of patients admitted for this symptom.152–154 In the vast majority, the clinical history is sufficiently typical to warrant the diagnosis without additional investigations. However, in some cases, tilt testing remains the key investigation used to diagnose the vasovagal origin of syncope. The methodology, complications and criteria for a positive response to tilt testing have already been reported in detail.129 Many studies have assessed the role of tilt testing in treatment selection, including pacing for vasovagal syncope. Data from controlled trials showed that 50% of patients with a baseline positive tilt test became negative when the test was repeated, whether the patient was receiving treatment or placebo.155–157 Moreover, acute studies were not predictive of the long-term outcome of pacing therapy.156 Finally, the mechanism of tilt-induced syncope was frequently different from that of spontaneous syncope recorded by an implantable loop recorder.158 These data show that tilt testing is of little or no value for assessing the effectiveness of treatments, particularly pacing.
1.4.2.1. Non-pacing therapy in vasovagal syncope
Despite vasovagal syncope being the most frequent of all causes of fainting, present treatment strategies are based on an incomplete understanding of the pathophysiology of the faint. In the majority of cases, patients who seek medical advice after having experienced vasovagal syncope mainly require reassurance and education regarding the benign nature of the condition. In particular, based on a review of their medical history, patients should be informed of the likelihood of syncope recurrence. Initial counselling should also include advice about adequate hydration and pre-monitory symptoms that may allow individuals to recognize an impending episode, so that they may take measures, such as lying down or using isometric manoeuvres, to avert or limit the consequence of a loss of consciousness. Pharmacological treatments in patients with vasovagal syncope, generally effective in non-randomized trials, have been consistently disappointing in randomized series.159,160
1.4.2.2. Indications for pacing in vasovagal syncope
Non-randomized trials
The rationale behind pacing for patients with vasovagal syncope is based upon the frequent observation of spontaneous, or tilt-induced, long ventricular pauses in those patients. However, head-up tilt findings have generally shown that pacing fails to prevent syncope, although it may prolong the prodrome.161,162 Nevertheless, pacing has been the object of a number of both small and large observational studies, either in single or multiple centres,161–164 demonstrating effectiveness in highly selected patient populations.
Randomized trials
The effectiveness of pacing has been studied in five multi-centre, randomized, controlled trials:165–169 the three non-blinded trials165–167 produced positive findings, whereas the two blinded studies168,169 had negative results. The strongest supportive evidence was provided by the North American Vasovagal Pacemaker Study (VPS)166 and the European VASIS trial.165 In the randomized, controlled Syncope Diagnosis and Treatment Study (SYDIT),167 the control arm patients were treated with atenolol and the pacemaker was superior to the beta-blocker in preventing recurrences of syncope. After the publication of these three trials, pacing was considered to be a tenable treatment for patients with frequent vasovagal syncope. However, both the VPS II168 and the Vasovagal Syncope and Pacing Trial (Synpace)169 produced contradictory findings. They differed from the previous trials because patients in the control arm received a permanent pacemaker that was switched off. Although there was a 30% reduction in syncope recurrence rate (95% CI –33 to 63%), the VPS II study failed to demonstrate a significant superiority for pacemaker therapy. In the Synpace study, syncope recurred in 50% of patients assigned to an active pacemaker and in 38% of patients assigned to an inactive pacemaker. As reported in the European guidelines for syncope,129 if the results of the five trials are put together, 318 patients were evaluated and syncope recurred in 21% (33/156) of the paced patients and in 44% (72/162) of the unpaced patients (P < 0.001). However, all the studies had weaknesses and further follow-up studies addressing many of these limitations, in particular the pre-implant selection criteria of patients who might benefit from pacemaker therapy, need to be completed before pacing can be considered an effective therapy in selected groups of patients with recurrent vasovagal syncope.
The inadequate effectiveness of pacing should not be surprising, since pacing can be expected to correct ventricular pauses but it cannot prevent hypotension due to vasodilation, which is frequently the dominant mechanism leading to loss of consciousness in vasovagal syncope. A recent study using the implantable loop recorder158 concluded that only about half of the patients had an asystolic pause recorded at the time of spontaneous syncope. The role of the implantable loop recorder in the selection of patients who may possibly benefit from cardiac pacing was evaluated in the ISSUE 2 study,170 which confirmed earlier data158 indicating that patients selected on the basis of asystolic spontaneous syncope on implantable loop recorder can benefit from pacing. In any case, it must be underlined that the decision to implant a pacemaker needs to be kept in the clinical context of a benign condition, which frequently affects young patients in whom pacemakers and leads for several decades may be associated with complications. Thus, cardiac pacing should be confined to an extremely select small group of patients affected by severe recurrent vasovagal syncope and prolonged asystole during Holter recording and/or tilt testing. Recommendations for cardiac pacing in vasovagal syncope are summarized in Table 1.4.3. If pacing is judged desirable for the treatment of vasovagal syncope, the device used should be one that has the capacity for programming modes that pace the ventricle whenever mandatory, from one cycle to the next (DDIR+hysteresis, DDD/AMC, DDD+AVD hysteresis),165 and control abrupt rate drops (rate drop response, rate smoothing, flywheel, etc.).166,167 It has been shown in small series that pacemakers with haemodynamic sensors (intracardiac impedance and peak endocardial acceleration) have the capability to diagnose the vasovagal episode earlier than at the moment of rate drop. AAI-like algorithms are contraindicated.
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1.4.3. Adenosine-sensitive syncope
Many series that included extensive evaluation have shown that 20–30% of patients with syncopal episodes have no precise diagnosis.153