Dualchamber pacemakers for symptomatic bradycardia due to sick sinus syndrome and/or atrioventricular block

Evidence-based recommendations on using dualchamber pacemakers for symptomatic bradycardia due to sick sinus syndrome or atrioventricular block.

# Guidance
This guidance has been partially updated by NICE technology appraisal guidance 324. See about this guidance for more information.
This guidance refers only to pacing for the primary indications of sick sinus syndrome and/or atrioventricular block, and does not cover more complex pacing indications.
Dual-chamber pacing is recommended for the management of symptomatic bradycardia due to sick sinus syndrome, atrioventricular block, or a combination of sick sinus syndrome and atrioventricular block, except:
in the management of atrioventricular block in patients with continuous atrial fibrillation; in this situation, single-chamber ventricular pacing is appropriate
in the management of atrioventricular block (atrioventricular block alone, or in combination with sick sinus syndrome), when patient-specific factors, such as frailty or the presence of comorbidities, influence the balance of risks and benefits in favour of single-chamber ventricular pacing.
The exception about the use of dual-chamber pacing in the management of sick sinus syndrome in patients in whom, after full evaluation, there is no evidence of impaired atrioventricular conduction  has been replaced by NICE technology appraisal guidance 324.# Clinical need and practice
Abnormal heart rhythms (dysrhythmias) are caused by disturbances in electrical impulse generation or by abnormal conduction between chambers of the heart  principally within the sinus node, atrioventricular (AV) node and the HisPurkinje network. Dysrhythmias may be fast (tachyrhythmias) or slow (bradyrhythmias), and regular or irregular.
Symptoms of bradycardia include faints, falls, dizziness and confusion (manifestations of hypotension), palpitations, fatigue on exertion, difficulty with breathing (dyspnoea) and chest pain. Common pathological conditions that cause bradycardia are sick sinus syndrome, atrioventricular block or a combination of the two.
Sick sinus syndrome is an irreversible dysfunction of the sinus node, a small area of the right atrium in which a small group of cells spontaneously depolarise and act as the heart's natural pacemaker. Sick sinus syndrome is characterised by impaired impulse formation, which is often the result of chronic fibrotic degeneration or calcification of the sinus node and/or the surrounding atrial tissues.
Atrioventricular block is a failure in the conduction of electrical impulses from the atria to the ventricles. This may be caused by conduction defects at the AV node (situated between the atria and ventricles), bundle of His and/or bundle branches. The AV node captures waves of depolarisation from the atria, which are then transferred to the ventricles via the bundles of His and the Purkinje system (branches of the conducting system). Atrioventricular block may be intermittent or permanent, and it can progress from minimal asymptomatic conduction delay to the ventricles (firstdegree), to partial (seconddegree) atrioventricular block, or complete (thirddegree) atrioventricular block, in which there is no conduction between the atria and ventricles. Although partial atrioventricular block is usually asymptomatic, it carries a high risk of progression to complete block.
The diagnosis of sick sinus syndrome and atrioventricular block is based on the correlation of symptoms with electrocardiographic findings (electrocardiogram  and ambulatory ECG or Holter monitoring). The prognosis of individuals with sick sinus syndrome or atrioventricular block is variable and difficult to predict because it may depend on the presence and severity of comorbidities (such as ischaemic heart disease) and the underlying cause of the conduction defect.
The prevalence of sick sinus syndrome is thought to be about 0.03% of the whole population, and increases with age. Estimates of the prevalence of atrioventricular block (based on clinical studies) range from 0.015% to 0.1%, although it is common for people to have coexisting abnormalities of both the sinus node and the AV node.
Pacemakers are indicated for use in the treatment of symptomatic bradycardia, and they control or replace the heart's intrinsic electrical activity. Some patients require intermittent pacing, whereas patients whose intrinsic heart rate is slow for most of the time require a pacemaker to pace most of their heartbeats.
Pacing systems are electrical devices that consist of a small batterypowered generator and one or more pacing leads that are in contact with the inner wall of the right atrium and/or the right ventricle. The pacemaker senses whether an intrinsic depolarisation has occurred. When this has not occurred, the pacemaker generates an electrical impulse, which is delivered to the heart muscle via the pacemaker leads to initiate contraction.
Pacemakers may be broadly classified as single or dualchamber devices, depending on whether leads are applied to one or two heart chambers. A range of additional features is also available, such as rate modulation (which allows the pacing rate to increase in response to physical activity or metabolic demand).
The British Pacing and Electrophysiology Group (BPEG) and the North American Society of Pacing and Electrophysiology have developed nomenclature that describes the different types of pacemakers (see Appendix D).
Pacemaker syndrome refers to a group of symptoms that includes nausea, palpitations, chest pain, fatigue, breathlessness, presyncope and syncope. The underlying cause of pacemaker syndrome is not fully understood. It is thought to be caused by loss of the heart's natural AV sequence, causing simultaneous contraction of the atria and ventricles. Under these circumstances, blood in the atrial chamber is not efficiently expelled into the ventricles, which results in large reductions in systolic blood pressure and cardiac output. There are difficulties in the diagnosis of pacemaker syndrome because of the overlap of the symptoms of pacemaker syndrome with many symptoms typical of cardiac disease, and with symptoms arising from comorbidities, particularly in elderly patients. Pacemaker syndrome may develop in patients with functional atria who receive a singlechamber ventricular pacemaker. Severe pacemaker syndrome can be eradicated by an upgrade to a dualchamber pacemaker, although this may be associated with an increased risk of perioperative complications. Patients with mild pacemaker syndrome often adapt over time to the condition and do not require a pacemaker upgrade.
Dualchamber pacing and singlechamber atrial pacing (in patients with sick sinus syndrome without atrioventricular block), as opposed to singlechamber ventricular pacing, are considered to be 'physiological' pacing modes because AV synchrony is maintained and the frequency of contractions of the atria and ventricles varies with metabolic demand, mimicking the heart's natural rhythm.
In the UK, about 26,000 pacemakers are implanted each year. In 2003, about 60% of implants were dualchamber pacemakers, 40% were singlechamber ventricular pacemakers, and 1% were singlechamber atrial pacemakers. Pacemakers may be implanted in patients of any age, although the average age of the recipients of pacemakers was 76 years in 2003.# The technology
Dualchamber pacemakers have pacing leads in the right atrium and ventricle. They are indicated for use in the treatment of atrioventricular block in the absence of continuous atrial fibrillation, and in sick sinus syndrome with atrioventricular block.
The unpublished draft report of the UKPACE cost utility analysis provided information on the aggregate acquisition (discounted) cost of pacemakers. The cost of pacemakers varied according to the type of device (see Appendix D for an explanation of pacemaker nomenclature): VVI 690, VVIR 1099, DDD 1365 and DDDR 2017, all excluding VAT. Atrial leads were 175 and ventricular leads were 172, excluding VAT.
The Association of British Healthcare Industries (ABHI) has advised that the average market (discounted) price of dualchamber pacemakers is between 1265 (for DDD) and 1713 (for DDDR), excluding VAT, compared with between 658 (for VVI) and 935 (for VVIR) for singlechamber pacemakers (See Appendix D for definitions of device types). The average price of leads is 169, excluding VAT. The Institute believes that these market prices represent a substantial discount on the list prices of these devices (which have not been provided to the Institute), and these prices may change over time because of environmental factors.# Evidence and interpretation
The Appraisal Committee (Appendix A) considered evidence from a number of sources (Appendix B).

# Clinical effectiveness
Outcomes against which the relative effectiveness of dualchamber and singlechamber pacing were assessed included the incidence of pacemaker syndrome, exercise capacity, functional status, quality of life (QoL), and incidence of atrial fibrillation, stroke, heart failure, mortality and adverse events.

## Dualchamber pacing versus singlechamber ventricular pacing
The Assessment Group searches identified 32 studies of dualchamber pacemakers versus singlechamber ventricular pacemakers. Four parallel randomised controlled trials (RCTs) allocated a total of 7006 patients to single or dualpacing modes (MOST and PASE studies), or single or dualchamber devices (CTOPP and the unpublished UKPACE study). Populations varied among the four RCTs and included patients with sick sinus syndrome with or without atrioventricular block (MOST), those with atrioventricular block alone (UKPACE), and mixed populations of patients with sick sinus syndrome and atrioventricular block (PASE and CTOPP). The CTOPP study randomised patients with sick sinus syndrome, with or without atrioventricular block to either singlechamber ventricular pacing or 'physiological' pacing where the device used maintains the heart's natural AV synchrony (dualchamber pacing in atrioventricular block with or without sick sinus syndrome, and singlechamber atrial pacing in sick sinus syndrome without atrioventricular block). Crossover trials (n = 28) randomised a total of 515 patients with sick sinus syndrome and/or atrioventricular block to dualchamber pacing or singlechamber ventricular pacing.
There was no statistically significant difference in the incidence of mortality or stroke with dualchamber pacing compared with singlechamber ventricular pacing in the four large RCTs. PASE and CTOPP were, however, conducted in a mixed population of patients with sick sinus syndrome and atrioventricular block, either alone or in combination. The results were presented for the populations as a whole and it was not possible to disaggregate the results for subgroups of patients.
The incidence of atrial fibrillation associated with dualchamber pacing compared with singlechamber ventricular pacing varied among the four large RCTs. The cumulative incidence of atrial fibrillation was up to 21.4% in the dualchamber pacing arm and 27.1% in the singlechamber ventricular pacing arm. The proportional reduction in the relative risk of atrial fibrillation with dualchamber pacing reached significance in two of the studies (MOST: adjusted hazard ratio 0.77, 95% confidence interval  0.64 to 0.92; and CTOPP: reduced annual risk with dualchamber pacing of 18%, 95% CI 5.5 to 43.6%). A metaanalysis of the results of three of the published RCTs (excluding the UKPACE study) demonstrated a statistically significant reduction in the incidence of atrial fibrillation with dualchamber pacing (odds ratio 0.76, 95% CI 0.65 to 0.90). A metaanalysis incorporating the results of the unpublished UKPACE trial was also made available, in confidence, to the Appraisal Committee.
The MOST study had the highest power to detect differences in the incidence of atrial fibrillation with dualchamber pacing and singlechamber ventricular pacing because it was a large trial in patients with sick sinus syndrome (thought to be one of the risk factors for atrial fibrillation) and the patients in this study had the highest incidence of prior nonchronic atrial fibrillation (up to 47%), which is also a risk factor for recurrence. The MOST study also reported a statistically significant higher incidence of atrial fibrillation with pacemaker dependency (compared with pacemaker nondependency) of 1% with dualchamber pacing (95% CI 0.2 to 1.8%; p = 0.01) and 0.7% with singlechamber ventricular pacing (95% CI 0 to 1.4%; p = 0.04) for every 1% increase in the proportion of ventricular beats paced.
Two published RCTs (MOST and CTOPP) reported a lower incidence of heart failure with dualchamber pacing (which reached significance in one of the studies) compared with singlechamber ventricular pacing. Results of the metaanalysis of these two studies showed no overall difference in the rate of heart failure with dualchamber pacing compared with singlechamber ventricular pacing (pooled odds ratio 0.83; 95% CI 0.66 to 1.05). A metaanalysis incorporating the unpublished UKPACE trial was also made available, in confidence, to the Appraisal Committee.
A metaanalysis of the 20 crossover studies showed a statistically significant improvement in exercise capacity with dualchamber pacemakers compared with singlechamber ventricular pacemakers (standardised mean difference 0.35, 95% CI 0.17 to 0.52; p < 0.0001). These benefits were evident when dualchamber pacemakers were compared with nonrateresponsive single chamber ventricular pacemakers (standardised mean difference 0.49, 95% CI 0.1 to 0.89; p < 0.01). A metaanalysis of exercise capacity with dualchamber pacing compared with singlechamber ventricular pacing demonstrated no difference in exercise capacity for patients older than 75 years (standardised mean difference 0.19; 95% CI 0.08 to 0.45), but there was a statistically significant improvement for patients younger than 75 years (standardised mean difference of 0.47; 95% CI 0.21 to 0.73). A metaanalysis of perceived exercise capacity reported in eight crossover studies showed a statistically significant improvement with dualchamber pacing (standardised mean improvement 0.68; 95% CI 0.29 to 1.08).
A metaanalysis of 12 studies reporting global measures of QoL, obtained using visual analogue scales, showed a statistically significant improvement in QoL with dualchamber pacing compared with singlechamber ventricular pacing. Three of the four RCTs evaluated QoL using the SF36 (UKPACE data on QoL was not available for the Assessment Report). The MOST study reported statistically significant improvements in QoL with dualchamber pacing in some of the QoL domains (improvement in physical function, physical role, social function, energy and emotional role, but not in mental health, pain and general health). The PASE study showed an improvement in QoL for domains of social function, physical role, emotional role, mental health and energy in the shortterm at 9month but not at 18month followup. The CTOPP study did not provide a separate analysis of dualchamber versus singlechamber ventricular pacing.
The four large RCTs reported large variations in the incidence of pacemaker syndrome with singlechamber ventricular pacing. The incidence reported in trials comparing pacing modes ranged from 18.3% to 26.1%, whereas trials comparing pacing devices reported a 4% rate of upgrade from singlechamber ventricular pacing to dualchamber pacing as a result of pacemaker syndrome. A metaanalysis (based on the assumption that pacemaker syndrome does not occur in dualchamber pacing) of the three published RCTs showed a statistically significant reduction in the incidence of pacemaker syndrome with dualchamber pacing compared with singlechamber ventricular pacing. This was confirmed by the pooled analysis of 14 crossover studies, which reported a statistically significant improvement in the symptoms of pacemaker syndrome with dualchamber pacing (standardised mean difference 0.88; 95% CI 1.13 to 0.62). A metaanalysis incorporating the results of the UKPACE trial was also made available, in confidence, to the Appraisal Committee.

## Dualchamber pacing versus singlechamber atrial pacing
Literature searches identified one small parallel RCT and two crossover RCTs that randomised a total of 211 patients with sick sinus syndrome to dualchamber pacing or singlechamber atrial pacing. The parallel RCT was a pilot study for a larger trial and was underpowered because recruitment was suspended before the target number of patients was reached.
The parallel RCT reported a statistically significant lower incidence of atrial fibrillation with singlechamber atrial pacing compared with dualchamber pacing (7.4% for singlechamber atrial pacing; 20% for dualchamber pacing; p = 0.03), but no statistically significant difference in mortality (allcause or cardiovascular mortality), the incidence of heart failure or stroke, functional status (based on specific activity scale scores) or QoL.
One crossover study in 19 patients showed a statistically significant improvement in exercise tolerance based on bicycle ergometer tests with singlechamber atrial pacing compared with dualchamber pacing (singlechamber atrial pacing 103 watts, SD 31, compared with dualchamber pacing 96 watts, SD 27; p < 0.05).
The incidence of development of atrioventricular block in patients who received singlechamber atrial pacing was variable, ranging from an annual incidence figure of 1.9% in the parallel RCT to a prevalence of 37% found during followup in one of the crossover studies.
The crossover studies reported no difference in the presence of symptoms of cardiac dysfunction (palpitations, dizziness, chest pain) with dualchamber pacing compared with singlechamber atrial pacing.

# Cost effectiveness
Literature searches identified one systematic review of the cost effectiveness of dualchamber pacing in patients with sick sinus syndrome, sick sinus syndrome with atrioventricular block or unspecified bradycardia, who were eligible for dualchamber or singlechamber pacing. The studies included in this review were of limited relevance because they did not incorporate effectiveness data from the recent large parallelgroup RCTs, because results were not presented as cost per qualityadjusted life year (QALY), and because of the technological developments in dualchamber pacing.
Three models were submitted to the Institute by consultees, and the Assessment Group also developed two separate Markov models that compared dualchamber with singlechamber pacing according to whether the underlying cause of bradycardia was sick sinus syndrome or atrioventricular block.
The ABHI submitted a discrete event simulation model of the costs and outcomes of DDDR compared with VVIR pacemakers in patients with sick sinus syndrome or atrioventricular block over a 5year time horizon. Dualchamber pacing was associated with an incremental cost of 42 and incremental benefits of 0.09 QALYs, giving an incremental cost effectiveness ratio (ICER) of 477 per QALY. Sensitivity analysis demonstrated that the incidence of severe pacemaker syndrome was the key driver of the cost effectiveness of dualchamber pacing: assumptions of 0% severe pacemaker syndrome with singlechamber pacing increased the ICER of dualchamber pacing to 10,444 per QALY.
Guidant submitted a Markov model of the costs and outcomes of dualchamber pacing compared with singlechamber ventricular pacing in a population of patients with sick sinus syndrome and atrioventricular block over a 10year time horizon. Dualchamber pacing was associated with an incremental cost of 742 and incremental benefits of 0.399 QALYs over 10 years compared with singlechamber ventricular pacing, giving an ICER of about 1800 per QALY. Sensitivity analysis of the cost effectiveness of dualchamber pacing in younger patients (50 years of age, over a 30year time horizon) showed the dominance of dualchamber pacing, which was less costly and generated more QALYs than did singlechamber pacing.
St Jude Medical submitted a model that compared the costs and outcomes of dualchamber with singlechamber pacing in patients with atrioventricular block and sick sinus syndrome, or sick sinus syndrome alone, over a 7.5year time horizon. Dualchamber pacing was associated with an incremental cost of 438, which was offset by a reduction in the cost of adverse events (severe pacemaker syndrome, stroke, heart failure and atrial fibrillation) demonstrating a cost saving of 182 for a mixed population of patients with sick sinus syndrome and atrioventricular block (or the avoidance of 101 adverse events), or a cost saving of 265 for a population of patients with sick sinus syndrome alone (or the avoidance of 56 adverse events). Sensitivity analysis demonstrated that the incidence of pacemaker syndrome had a major effect on the cost effectiveness of dualchamber pacing.
The Assessment Group developed separate models that compared the cost and outcomes of dualchamber compared with singlechamber pacing in populations of patients with sick sinus syndrome and atrioventricular block over a 10year time horizon. The atrioventricular block model compared dualchamber with singlechamber ventricular pacing, and the sick sinus syndrome model compared dualchamber with singlechamber atrial pacing. The models were similar in structure. A hypothetical cohort of 2000 75yearold patients entered each model immediately before pacemaker implantation, during which they could develop perioperative complications. After successful pacemaker implantation, patients progressed through the model in 1monthly cycles between the following health states: postoperative complications; well with pacemaker; health states associated with complications (atrial fibrillation, heart failure, stroke), which could occur in any arm of the model; mild and severe pacemaker syndrome (which occurred only in the singlechamber ventricular pacing arm); generator expiry; upgrade to a dualchamber pacemaker; and death. Patients progressed to death from any health state, although the transition probability was specific to the previous health state (for example, risk of death from stroke) where possible.
Baseline estimates of the effectiveness of singlechamber pacing were based on trials identified in the systematic review. The relative effectiveness of dualchamber pacing was incorporated into the model by applying the relative risk estimates from the metaanalysis or from individual trials to the baseline parameters.
The cost of pacemakers was based on a survey of the annual hardware cost of all pacemakers implanted from 10 hospitals that were involved in the UKPACE study. These costs represent the aggregate acquisition cost of pacemakers contained in the draft report of the unpublished UKPACE costutility analysis (see Section 3.2). The proportion of rateresponsive single and dualchamber pacemakers used in the model was based on the proportion of rateresponsive and nonrateresponsive devices reported in the clinical trials. In the ventricular pacing arm of the model, 24% of devices were VVI and 76% of devices were VVIR, and in the dualchamber arm, there was an equal proportion of DDD and DDDR pacemakers. The cost of the implantation procedure was estimated using cost data from the Resource Cost Initiative and incorporated differences in the costs of dual and singlechamber devices.
Utility estimates were based on the PASE trial (in which a time tradeoff method elicited patient preferences for different health states) or reports of studies in the Harvard Catalogue of Preference Scores. Utility for the cycle of pacemaker implantation was 0.76, and the utility of 'well with pacemaker' was 0.925. All complications (including pacemaker upgrade or replacement) were associated, on the basis of clinician's estimates, with a utility decrement of 0.01.
The Assessment Group model contained a number of assumptions related to the incidence of complications with different pacing modes. Pacemaker syndrome (4% severe pacemaker syndrome and 22% mild pacemaker syndrome) occurred only in the singlechamber ventricular pacing arm. Patients with severe pacemaker syndrome were upgraded to a dualchamber pacemaker. Mild pacemaker syndrome was chronic. The progression of atrioventricular block in sick sinus syndrome was modelled only in the singlechamber atrial pacing arm; these patients were upgraded to a dualchamber device. When atrial fibrillation occurred with dualchamber pacing, devices were reprogrammed to singlechamber ventricular pacing and patients assumed the same risk of atrial fibrillation, stroke and heart failure as with singlechamber ventricular pacing.
The basecase scenario of the atrioventricular block model was based on the UKPACE survey of the market price of pacemakers, and the assumption that mild pacemaker syndrome did not resolve (these patients had a utility of 0.80 for the remainder of their lifetime). Dualchamber pacing was associated with an increased cost of 700 and an additional 0.082 QALYs at 5 years, giving an ICER of 8500 per QALY. The ICER of dualchamber pacing decreases as benefits are accrued over a 10year time horizon, giving an ICER of 5500 per QALY.
Oneway sensitivity analysis demonstrated that the variations in implantation cost, and rates of background mortality, perioperative complications, atrial fibrillation, heart failure, stroke and generator replacement had little effect on the cost effectiveness of dualchamber pacing in atrioventricular block. However, the cost effectiveness of dualchamber pacing is sensitive to variations in price difference between dual and singlechamber pacemakers and assumptions about the incidence and resolution of mild pacemaker syndrome. A sensitivity analysis that evaluated the cost effectiveness of dualchamber pacing based on the market price of devices supplied by the ABHI (Section 3.3) resulted in ICERs of 7000 per QALY (over a 5year time horizon) and 4600 per QALY (over a 10year time horizon). Another sensitivity analysis varied the price of pacemakers to approximate the minimum (dualchamber 5200, singlechamber atrial and ventricular pacemaker 4600), average (dualchamber 6500, singlechamber atrial and ventricular pacemaker 4900) and maximum (dualchamber 8400 and singlechamber atrial and ventricular pacemaker 5300) list prices of pacemakers. At the minimum and average assumed list prices of pacemakers, dualchamber pacing was associated with an ICER of less than 16,000 per QALY at 5 years. However, the ICER rose to 34,000 per QALY when the assumed maximum cost of devices was used. Another sensitivity analysis assumed that 50% of cases of mild pacemaker syndrome resolve per cycle into a controlled state (compared with 0% in the base case). In this scenario, 90% of cases of mild pacemaker syndrome resolve within 4 months, and the ICER is increased to 36,000 per QALY at 5 years and 18,000 per QALY at 10 years.
The results of the model of dualchamber pacing in sick sinus syndrome demonstrated that dualchamber pacing is dominated by singlechamber atrial pacing, because atrial pacing generates more QALYs and is less costly than dualchamber pacing. Sensitivity analysis showed that singlechamber atrial pacing dominates dualchamber pacing in all scenarios.

# Consideration of the evidence
The Committee reviewed the evidence available on the clinical and cost effectiveness of dualchamber pacing, having considered evidence on the nature of the condition and the value placed on the benefits of dualchamber pacing by users, those who represent them, and clinical experts. The discussions were also informed by consideration of the clinical appropriateness of pacing for different underlying causes of bradycardia and therefore the need to consider comparisons with singlechamber ventricular pacing separately from those with singlechamber atrial pacing. It was also mindful of the need to take account of the effective use of NHS resources.
The Committee considered evidence on the benefits and risks of dualchamber pacing compared with singlechamber ventricular pacing. It discussed the difficulties in interpreting the evidence from analyses in mixed populations and acknowledged that some of the large RCTs used pacing modes that may not be clinically appropriate (for example, singlechamber ventricular pacing for sick sinus syndrome without atrioventricular block). The Committee was also aware that RCT evidence from patients with a mean age of 7380 years may not be applicable to younger patients. The Committee heard from experts that dualchamber pacemakers are associated with a higher incidence of perioperative complications and that the lifetime of a dualchamber pacemaker is likely to be 1 year less than a singlechamber ventricular pacemaker. The Committee accepted expert testimony of the significant quality of life and clinical benefits associated with dualchamber pacing (reduction in the rate of atrial fibrillation, improved exercise capacity and a reduction in the incidence of pacemaker syndrome). Overall the Committee concluded that these benefits outweighed the evidence from the experts on the increased risk of perioperative complications with dualchamber pacemakers and potential need to replace dualchamber pacemakers up to 1 year earlier than singlechamber ventricular pacemakers.
The Committee reviewed all the data and economic models on the cost effectiveness of dualchamber pacing compared with singlechamber ventricular pacing in atrioventricular block. The Committee discussed the Assessment Group models, particularly the incidence of and utilities associated with mild and severe pacemaker syndrome, which were key drivers of the cost effectiveness estimates. The Committee heard from experts that the 4% incidence of severe pacemaker syndrome was appropriate, but the model may overestimate the incidence of mild pacemaker syndrome in singlechamber ventricular pacing, and pacemaker syndromelike symptoms may also occur with dualchamber pacing, albeit infrequently. The Committee also considered that the disutility associated with mild pacemaker syndrome, and therefore the cost effectiveness of dualchamber pacing, (utility of 0.80 compared with 0.62 for severe pacemaker syndrome, and 0.925 for 'well with pacemaker') may have been overestimated in the Assessment Group model. Although the Assessment Group model may have overestimated the cost effectiveness of dualchamber pacing, the Committee concluded that dualchamber pacing is cost effective even when conservative assumptions around the effects of pacemaker syndrome are considered (see sensitivity analysis discussion, section 4.2.12).
The Committee considered the cost effectiveness of dualchamber pacing compared with singlechamber ventricular pacing based on the market price of devices supplied by the ABHI, and the likely list price of devices. It considered that although the ICER for dualchamber pacing over singlechamber ventricular pacing (based on the list price of devices) in atrioventricular block is likely to be significantly higher than identified in the Assessment Group model's central estimates, dualchamber pacing is still likely to be a costeffective alternative to singlechamber ventricular pacing.
The Committee agreed with expert opinion that dualchamber pacing is clinically inappropriate for the treatment of patients with impaired atrioventricular conduction (atrioventricular block alone, or in combination with sick sinus syndrome) who also present with continuous atrial fibrillation. In these patients atrial pacing is ineffective and tracking of the high atrial rate may result in an inappropriately rapid ventricular pacing rate. Singlechamber ventricular pacing is the clinically appropriate pacing mode for these patients.
The Committee considered the evidence on the clinical effectiveness of dualchamber pacing compared with singlechamber atrial pacing for sick sinus syndrome. The Committee also acknowledged expert testimony indicating that in this population, singlechamber ventricular pacing is not clinically appropriate because of the risk of pacemaker syndrome. The available evidence indicated that singlechamber atrial pacing is likely to be more clinically effective than dualchamber pacing in the treatment of sick sinus syndrome with normal AV conduction because it is associated with a lower rate of atrial fibrillation and with improved exercise tolerance. This was supported by other evidence from published studies that indicated the superiority of singlechamber atrial pacing over singlechamber ventricular pacing in sick sinus syndrome.
Although the evidence indicated the benefits of singlechamber atrial pacing, the Committee was aware that some people with sick sinus syndrome who receive a singlechamber atrial pacemaker may subsequently develop atrioventricular block, and would then require an upgrade to a dualchamber pacemaker. The Committee recognised that this may mean patients need a second operation, but heard from experts that although the risk of late development of atrioventricular block in patients with sick sinus syndrome is difficult to predict, there were risk factors that could be identified by a thorough evaluation of atrioventricular conduction. The Committee was advised that this evaluation would usually include, as a minimum, the assessment of the standard ECG for the presence of conduction abnormalities. Additionally it may also involve, during pacemaker insertion, pacing of the atrium at different rates (usually between 100 and 130 beats per minute) in order to assess the onset of the Wenckebach phenomenon as a predictor of failure in atrioventricular conduction. The Committee was advised that, provided a patient receiving a single chamber atrial device undergoes such an evaluation and exhibits none of the risk factors, the incidence of subsequent development of atrioventricular block in patients with sick sinus syndrome is likely to be as low as 12% per annum. Experts advised that up to 20% of patients with sick sinus syndrome do not have any evidence of atrioventricular block (after evaluation with provocation testing), and the Committee therefore concluded that singlechamber atrial pacing is suitable for these patients.
The Committee appreciated that rateresponsive dual and singlechamber pacemakers are more costly but may confer additional benefits compared with nonratemodulating devices. However, based on the evidence presented and the costeffectiveness analysis, the Committee concluded that decisions about whether to implant a rateresponsive or a nonrateresponsive device should be made using clinical judgement on an individual patient basis.
In summary, the Committee concluded that, for most people who have sick sinus syndrome with atrioventricular block, and for those with atrioventricular block without continuous atrial fibrillation, dualchamber pacing is preferred to singlechamber pacing. The Committee, however, recognised that in certain specific circumstances, singlechamber pacemakers were more clinically appropriate. Singlechamber atrial pacing is the clinically appropriate pacing mode for people with sick sinus syndrome without atrioventricular block in people who had been fully assessed (for example, using Wenckebach rate testing) for the presence of, and risk factors related to, the development of atrioventricular block. In this group, singlechamber ventricular pacing is contraindicated and dualchamber pacing is associated with an increased incidence of atrial fibrillation. Similarly, singlechamber ventricular pacing is the clinically appropriate pacing mode for people with atrioventricular block with continuous atrial fibrillation (dualchamber pacing is contraindicated in this group).
The Committee also concluded that, in the management of patients with atrioventricular block (atrioventricular block alone, or in combination with sick sinus syndrome), the presence of additional factors (such as frailty and comorbidities) may need to be taken into account in decision making. Under some circumstances these factors may affect the decision about the clinical appropriateness of dual or singlechamber ventricular pacing, which should then be made on an individual patient basis, taking into consideration the risks and benefits associated with each pacing mode.# Recommendations for further research
The publication of the UKPACE trial will provide additional data on a number of outcomes including quality of life with dualchamber pacemakers compared with singlechamber ventricular pacemakers.
The ongoing DANPACE trial will provide additional information on the effectiveness of dualchamber pacing compared with singlechamber atrial pacing in patients with sick sinus syndrome without atrioventricular block.
The Institute recommends that further studies evaluate the incidence of mild pacemaker syndrome, and utilities associated with health states of mild and severe pacemaker syndrome.
Future studies should evaluate the effectiveness of rateresponsive compared with nonrateresponsive pacemakers.
Further research is also recommended into the predictors for the development of atrioventricular block in sick sinus syndrome, to enable clinicians to determine people for whom singlechamber atrial pacing is appropriate.
Further studies should evaluate the effectiveness of dual and singlechamber pacing at followup beyond 5 years (where possible, up to 10 years) for outcomes of mortality, stroke, heart failure, atrial fibrillation and pacemaker syndrome.# Implications for the NHS 
About 25,000 pacemakers are implanted every year in the UK; three quarters of these are first implants, and one quarter are replacements.
The current hardware cost of pacemaker implantation based on the market cost of pacemakers and leads (see Section 3.2) and the proportion of pacemaker types implanted is about 43 million per year. This may underestimate the annual cost of pacemakers because the market price represents a substantial discount on the list price of pacemakers. However, the Institute does not have access to information on the list price of pacemakers.
Dualchamber pacemakers accounted for nearly 60% of the pacemakers implanted in 2003. The anticipated additional cost of implementing this guidance is dependent on the increased acquisition cost of dualchamber pacemakers, the number of patients with continuous atrial fibrillation who are not suitable for dualchamber pacing, and the likely uptake of dualchamber pacing. The uptake of dualchamber pacing is likely to vary between 70% and a theoretical maximum of 90%, for which the implementation cost varies between about 8 million and 10 million per year, based on the current implantation rate of pacemakers. This does not take into consideration potential differences in the staff and theatre costs between procedures for implanting dual and singlechamber pacemakers. The Institute was made aware that dualchamber pacing may be associated with slightly more followup, which may have implications for the workload of staff in some trusts. However, the Institute does not have sufficient information to estimate the national impact of this guidance on human resources.# Related guidance
The Institute has published the following related Technology Appraisals:
Implantable cardioverter defibrillators (ICDs) for the treatment of arrhythmias  review of NICE Technology Appraisal No 11. (Replaced by NICE technology appraisal guidance 95)
Cardiac resynchronisation therapy for the treatment of heart failure. NICE technology appraisal guidance 120 (2007)
The Institute has pubslished one related Clinical Guideline:
Atrial fibrillation: risk assessment, diagnosis, treatment and review. NICE clinical guideline 36 (2006)# Review of guidance
The review date for a technology appraisal refers to the month and year in which the Guidance Executive will consider whether the technology should be reviewed. This decision will be taken in the light of information gathered by the Institute, and in consultation with consultees and commentators
The guidance on this technology will be considered for review in January 2007.Andrew DillonChief ExecutiveFebruary 2005# Appendix C Detail on criteria for audit of the use of dualchamber pacemakers for symptomatic bradycardia due to sick sinus syndrome and/or atrioventricular block

# Possible objectives for an audit
An audit could be carried out to ensure that dualchamber pacing is used appropriately for the management of symptomatic bradycardia due to sick sinus syndrome and/or atrioventricular block.

# Possible patients to be included in the audit
An audit could be carried out on people with symptomatic bradycardia associated with sick sinus syndrome, atrioventricular block, or a combination of sick sinus syndrome and atrioventricular block who are seen in a reasonable period for audit, for example 3 or 6 months. People with more complex pacing indications should be excluded from this audit.

# Measures that could be used as a basis for an audit
The measure that could be used in an audit of the management of symptomatic bradycardia to ensure that dualchamber pacing is used appropriately as follows.
Criterion
Standard
Exception
Definition of terms
. Dualchamber pacing is used for the management of symptomatic bradycardia associated with any of the following:
a. sick sinus syndrome (SSS)
b. atrioventricular block (AVB)
c. a combination of SSS and AVB
% of people with symptomatic bradycardia associated with SSS, AVB or a combination of SSS and AVB
A. The patient has SSS with no evidence of impaired atrioventricular conduction and singlechamber atrial pacing is used or
B. The patient has AVB with continuous atrial fibrillation and the risk of inappropriate atrial capture is high and singlechamber ventricular pacing is used
C. The patient has AVB (alone or in combination with SSS) and singlechamber ventricular pacing is preferred by the clinician on the basis of consideration of the risks and benefits for the patientspecific factors
Sick sinus syndrome is also known as sinus node dysfunction.
See Appendix D for pacemaker nomenclature.
Patients who meet exception A must have had a full evaluation, which clinicians will need to define locally for audit purposes.
Clinicians will need to agree locally on how consideration of dual or singlechamber pacing is documented for audit purposes, for example, for exception C with reference to patient factors such as frailty or the presence of comorbidities that may influence the balance of risks and benefits.

# Calculation of compliance
Compliance (%) with each measure described in the table above is calculated as follows.
Number of patients whose care is consistent with the criterion plus number of patients who meet any exception listed
x 100
Number of patients to whom the measure applies
Clinicians should review preliminary compliance with each measure and the patients whose care was not consistent with the audit measure. Clinicians may use their clinical judgement and conclude that some patients whose care is not consistent with the audit measure nevertheless were provided with the most appropriate care for their conditions. Clinicians should then decide whether practice can be improved, agree on a plan to achieve any desired improvement and repeat the measurement of actual practice to confirm that the desired improvement is being achieved.# Appendix D Pacemaker nomenclature
In 1987, the North American Society of Pacing and Electrophysiology (NASPE) and the British Pacing and Electrophysiology Group (BPEG) set up the NBG (NASPE/BPEG Generic) code to describe different pacing modes. To incorporate new technologies such as dualchamber pacing, this code was updated in 2002.
The first letter of the code signifies the chamber being paced:O = noneA = atriumV = ventricleD = dual (A + V)(Manufacturers' designation only: S = single )
The second letter signifies the chamber being sensed:O = noneA = atriumV = ventricleD = dual (A + V)(Manufacturers' designation only: S = single )
The third letter signifies the response to sensing: O = noneI = inhibitedT = triggered D = dual (T + I)
The fourth letter signifies rate modulation: O (or no letter) = noneR = rate modulation
The fifth letter signifies multisite pacing:O (or no letter) = noneA = atriumV = ventricleD = dual (A + V)
For example, 'DDD' indicates dualchamber pacing with no rate modulation or multisite pacing. 'AAI' indicates atrial pacing inhibited by sensed spontaneous atrial depolarisations; no rate modulation or multisite pacing.# Changes after publication
November 2014: This guidance has been partially updated by technology appraisal guidance 324.
March 2014: minor maintenance
March 2012: minor maintenance# About this guidance
NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.
This guidance has been partially updated by NICE technology appraisal guidance 324. TA324 recommends dual chamber pacemakers for people with symptomatic bradycardia due to sick sinus syndrome and no evidence of atrioventricular block.
We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.
Your responsibility
This guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.
Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.
Copyright
 National Institute for Health and Clinical Excellence 2014. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and notforprofit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.