Dualchamber pacemakers for symptomatic bradycardia due to sick sinus syndrome without atrioventricular block

Evidence-based recommendations on dual-chamber pacemakers for treating symptomatic bradycardia caused by sick sinus syndrome without atrioventricular block.

# Guidance 
This guidance partially updates NICE technology guidance TA88 issued in February 2005. See about this guidance for more information.
Dualchamber pacemakers are recommended as an option for treating symptomatic bradycardia due to sick sinus syndrome without atrioventricular block.# Clinical need and practice
Bradycardia is a slow heart rate, defined as a heart rate of less than 60 beats per minute. Bradycardia can be caused by a range of factors, including diseases such as:
sick sinus syndrome  a number of abnormal heart rhythms caused by an irreversible dysfunction of the sinus node (the heart's natural pacemaker), including:
sinus arrest or pause, in which the sinus node occasionally does not generate electrical impulses, from a period lasting a couple of seconds to several minutes
sinoatrial exit block, in which the sinus node generates electrical impulses normally, but the signal is blocked before it leaves the sinus node
alternating bradyarrhythmias and tachyarrhythmias (a fast heart rate), such as bradycardiatachycardia syndrome
atrioventricular block (a condition in which electrical impulses from the sinus node are slowed or blocked). Atrioventricular block can occur independently from sick sinus syndrome, and so people with symptomatic bradycardia due to sick sinus syndrome may also have or develop atrioventricular block.
The most commonly identified causes of abnormal heart rhythms are age, ischaemic heart disease, heart valve disorders and heart failure. If untreated, symptomatic bradycardia may lead to fatigue, fainting, palpitations, dizziness, heart failure and an increased risk of mortality.
Sick sinus syndrome is difficult to diagnose because of the intermittent symptoms, and also because symptoms are usually nonspecific and observed in other disorders. Diagnosis is made using electrocardiograms (ECGs). Because abnormalities may be intermittent, Holter monitoring (ECG monitoring for 24 to 48 hours) or event recorders may be used.
The prognosis of individuals with sick sinus syndrome is variable and difficult to predict, depending on the underlying cause and the presence and severity of comorbidities (such as ischaemic heart disease). For most people, the disease is idiopathic (that is, the cause is unknown) and progressive. People whose disease is not symptomatic do not need therapy; however, once the disease becomes symptomatic, it can have a significant impact on quality of life, and the only effective treatment is permanent implantation of a pacemaker. Most people who need a pacemaker implanted are older than 60 years.
The prevalence of sick sinus syndrome is thought to be about 0.03% of the whole population, and increases with age. However, both the prevalence of bradyarrhythmias due to sick sinus syndrome needing permanent pacemaker implant, and the prevalence of sick sinus syndrome with atrioventricular block, is unknown. Hospital episode statistics data from October 2012 to September 2013 included 2490 patients with a primary diagnosis of sick sinus syndrome in NHS hospitals in England. Sick sinus syndrome usually occurs in older adults, but it can affect people of any age, and affects men and women equally. The incidence of atrioventricular conduction abnormalities also increases with increasing age.

# Current management
Pacemakers are electrical devices that consist of a small batterypowered generator and 1 or more pacing leads that are in contact with the inner wall of the right atrium and/or the right ventricle. The primary aim of permanent pacing is to prevent the heart from beating too slowly. An important secondary aim is to reproduce, as far as possible, the function of the heart's normal electrical conduction system, which coordinates the way the heart muscle contracts. Pacemaker devices may be broadly classified as single or dualchamber, depending on whether leads are applied to 1 or 2 heart chambers. Dualchamber pacemaker devices are attached to both chambers of the heart and may be used in either dualchamber pacing mode (in which both the right atrium and ventricle are paced, which mimics the natural pacing rhythm of the heart) or singlechamber pacing mode (where only 1 chamber of the heart is paced, either the atrium or the ventricle). Singlechamber pacemaker devices may be either singlechamber atrial devices or singlechamber ventricular devices, and may only be used in the mode (that is to pace the chamber) where the lead was originally placed. Pacemakers may also be rate modulating (that is, able to sense and adapt the rate of pacing to the level of physical exertion).
NICE technology appraisal guidance 88 (hereafter referred to as TA88) recommended the use of singlechamber atrial pacemakers for treating sick sinus syndrome in people in whom, after full evaluation, there was no evidence of impaired atrioventricular conduction. The purpose of this part review is to update this recommendation because the DANPACE trial, which was published after the publication of TA88, has provided additional evidence comparing dual with singlechamber atrial pacemakers for this population.
In 2012/13 in England, more than 20,000 people had a single or a dualchamber pacemaker fitted. Sick sinus syndrome was the fourth most prevalent primary diagnosis (9.5%) after atrial fibrillation and flutter (22.5%), complete atrioventricular block (18.8%) and second degree atrioventricular block (10.6%). For people with a primary diagnosis of sick sinus syndrome (2490 patients), 67.5% had implantation of a dualchamber pacemaker, 14.8% had implantation of a singlechamber pacemaker and 2.2% had a reoperation of an existing implanted pacemaker.# The technology 
Dualchamber pacemakers are small batterydriven devices implanted in the chest with pacing leads inserted in the right atrium and ventricle. The pacing leads have sensors that detect the natural heartbeat and send that information to a small computer in the pacemaker. The pacemaker uses this data to send signals back to the heart to help it beat regularly. There are several different types of dualchamber pacemaker depending on whether they inhibit or trigger heart beats (in response to sensed electrical activity in the heart) and whether they are rate responsive (in which the pacing rate varies according to physical activity).
Dualchamber pacemakers may be associated with a number of adverse reactions. The need for an additional lead in dual compared with singlechamber pacemakers might lead to an associated increased risk of complications, such as lead displacement, puncture of the lung when placing the leads and infection of the pacemaker pocket or the leads. Complications arising after pacemaker implantation may include dysfunction of the pacemaker or of the leads (that is, failure to pace or sense appropriately), infection or erosion of the pacemaker site or its leads and the development of pacemaker syndrome, stroke, heart failure or atrial fibrillation. Reoperation may be needed as a result of a complication or endofbattery life. The complication rate associated with a reoperation to remove or replace leads is higher than that associated with initial implantation. Battery replacement has a very low complication rate when the leads do not need to be removed or replaced.
The acquisition cost of pacemakers depends on the particular model. The Association of British Healthcare Industries estimates an average cost of dualchamber pacemaker devices of 1265, and for singlechamber atrial pacemaker devices a price of 718. Costs may vary in different settings because of negotiated procurement discounts.# Evidence and interpretation
Details of membership of the Appraisal Committee are given in section 7, and a list of the sources of evidence used in the preparation of this document is given in section 8.

# Clinical effectiveness
The Assessment Group conducted a systematic review of the literature to identify studies evaluating the clinical effectiveness and safety of dualchamber pacemakers compared with singlechamber atrial pacemakers for the treatment of symptomatic bradycardia due to sick sinus syndrome with no evidence of atrioventricular block, identifying a total of 6 relevant randomised controlled trials. Three of the trials (Albertsen et al. 2008, DANPACE 2011 and Nielsen et al. 2003) were parallel group trials (see sections 4.2 to 4.5) and 3 of the trials (Gallick et al. 1994, Lau et al. 1994 and Schwaab et al. 2001) were crossover trials (see sections 4.6 to 4.9).

## Parallel group trials
The parallel group trials randomised participants to receive either a singlechamber atrial pacemaker device or a dualchamber pacemaker device. The trials varied in size from 50 to 1415 randomised participants, the mean age was similar across the 3 parallel trials and between study arms (7274 years), and either all or most of the people within each trial had the pacemakers programmed with the rateadaptive function activated. All parallel randomised controlled trials excluded patients if they had chronic atrial fibrillation, atrioventricular block, carotid sinus syndrome, vasovagal syncope, bundle branch block, surgery, short life expectancy, dementia or cancer. At baseline, most of the participants had their condition classed (according to the New York Heart Association  class  used to classify the extent of heart failure according to the severity of symptoms) as I or II (96%) at the end of followup with no or mild symptoms of heart failure. The Assessment Group conducted randomeffect model metaanalyses for the parallel trials where appropriate, generating odds ratios.
Albertsen et al. (2008) compared the impact of dualchamber pacemaker devices (n=26) with singlechamber atrial pacemaker devices (n=24) on left ventricular desynchronisation in people with sick sinus syndrome, including those with sinus arrest or sinoatrial block, bradycardiatachycardia syndrome and sinus bradycardia. The study was based in Denmark, with a followup of 12 months. The primary outcome was changes in left ventricular dyssynchrony (that is, the level of delay or difference in the timing of contraction in the different segments within the left ventricle) from baseline to 12 months of followup. Secondary outcomes included the measurement of Nterminal prohormone of brain natriuretic peptide (a hormone released in response to heart problems) and a 6minute walk test.
DANPACE (2011) compared rateresponsive dualchamber pacemakers (n=708) with rateresponsive singlechamber atrial pacemakers (n=707) for treating sick sinus syndrome (including those with sinoatrial block or sinusarrest, sinus bradycardia and bradycardiatachycardia). The study was based in Denmark, the UK and Canada, and there was a mean followup of 5.4 years. The primary outcome was death by any cause. Secondary outcomes included paroxysmal or chronic atrial fibrillation, stroke, cardiovascular mortality, need for pacemaker reoperation and quality of life.
Nielsen et al. (2003) compared rateresponsive dualchamber pacemakers with rateresponsive singlechamber atrial pacemakers (n=54) for treating sick sinus syndrome (including those with sinus bradycardia, sinoatrial block and bradycardiatachycardia syndrome). The trial had 2 dualchamber pacemaker arms, with different programmed atrioventricular block delay: short atrioventricular delay (less than 150 milliseconds, n=60) and long atrioventricular delay (a fixed delay of 300 milliseconds, n=63). The study was based in Denmark and mean followup was 2.9 years. The primary outcome was changes in left atrial size and left ventricular size and function during followup. Secondary outcomes were cardiographic (changes in left atrial volume, left ventricular volume and left ventricular ejection fraction) and clinical (atrial fibrillation, thromboembolism, allcause and cardiovascular mortality, and congestive heart failure). The Assessment Group noted that there were some imbalances between the trial arms for the subtypes of sick sinus syndrome.

## Crossover trials
In the crossover trials, all participants had a dualchamber pacemaker device implanted, and were then randomised to either single or dual pacing modes and then later crossed over to the alternative pacing mode. Lau et al. (1994) and Schwaab et al. (2001) randomised participants before implant by pacing programme, and Gallick et al. (1994) randomised participants who recently had a pacemaker fitted. The Assessment Group reported that they were unable to undertake metaanalyses on the crossover trials because of a lack of relevant data in all studies.
Gallick et al. (1994) compared dualchamber pacing mode with singlechamber atrial pacing mode in people with sick sinus syndrome (including those with sinus node disease; n=12), using ventricular function to study the immediate effects of pacing mode during exercise. Outcomes were exercise and haemodynamic parameters. The trial measured haemodynamic effects during bicycle exercise, initially in 1 pacing mode and, after 0.5 to 1 hour rest, after which the exercise was repeated in the other pacing mode. Gallick et al. excluded people with evidence of atrioventricular node disease or who were unable to exercise. The study location was not reported, and the followup was less than 1 day.
Lau et al. (1994) compared dualchamber, singlechamber atrial and singlechamber ventricular pacing modes for people with sick sinus syndrome (n=15), studying the effects of pacing modes and intrinsic conduction on physiological responses, arrhythmias, symptoms and quality of life. Participants spent 4 weeks in each pacing mode before crossing over to the other pacing mode. Lau et al. did not report specific exclusion criteria. The study location was not reported, and followup was 3 months. Outcomes were Holter monitoring, ambulatory blood pressure monitoring, symptoms and qualityoflife assessments.
Schwaab et al. (2001) compared dualchamber with singlechamber atrial pacing mode for people with bradycardiatachycardia syndrome (n=21). Participants spent 4 weeks in each pacing mode before crossing over to the other pacing mode. Participants had to have chronotrophic incompetence (that is, an inability of the heart to increase its rate appropriately with increased activity, leading to exercise intolerance), have experienced at least 2 documented episodes of atrial tachyarrhythmia and be on antiarrhythmic medication for prevention of atrial flutter or atrial fibrillation. The study was based in Germany, and the followup period was 3 months. Outcomes included quality of life, left ventricular outflow, bicycle cardiopulmonary exercise testing (to assess outcomes including exercise duration), number of episodes and total duration of atrial tachyarrhythmia, incidence of atrioventricular block type I, II or III and maximum duration of the longest atrioventricular pause, and percentage of paced atrial and ventricular beats.

## Parallel and crossover trial quality
The Assessment Group noted that the quality of the trials was generally high, with appropriate trial design and methodology, and that the trials appeared to be appropriately randomised with a low number of participants excluded or lost to followup. The baseline characteristics were similar between the trial arms and across the parallel and crossover trials. In particular, DANPACE (2011) was considered to be a relatively large trial of good quality with a long followup, which represents the best available evidence comparing dualchamber pacing with singlechamber atrial pacing for people with sick sinus syndrome without evidence of atrioventricular block. However, the Assessment Group noted several limitations of the trials. General limitations included that data were not reported consistently across the trials. Trials were either open label, or blinding to pacing modes was unclear (possibly increasing the risk of bias to subjective outcomes such as quality of life and exercise capacity) and the programmed atrioventricular block delay in the dualpacing mode differed greatly between the trials and study arms, adding heterogeneity to the trials. In addition, new technologies in this area develop rapidly, therefore the implants used in the trials may now be superseded, limiting applicability of the results to current devices. Weaknesses of the parallel trials included that Albertsen et al. (2008) and Nielsen et al. (2003) had small sample sizes and short followup in comparison with DANPACE (2011; giving them little weight in metaanalyses), and both DANPACE and Nielsen et al. were underpowered to show a statistically significant difference in the primary outcome (allcause mortality in DANPACE, and changes in left atrial size and left ventricular size and function in Nielsen et al.) because they were terminated early. Recruitment for Nielsen et al. was stopped after randomisation of 177 patients (from a target of 450) because recruitment for DANPACE had started. Recruitment for DANPACE was stopped after randomisation of 1415 patients (of a target of 1900) because of the increasing use of dualchamber pacemakers with additional features that were not permitted in the trial. Limitations of the crossover trials included that the trials had a small number of participants (n=1221) and short durations (up to 3 months), which limited the possible outcomes and reduced the power to detect differences between pacing modes.

# Clinical effectiveness
The Assessment Group presented the results of the clinical effectiveness of the trials. Where possible for dichotomous outcomes, the Assessment Group undertook metaanalyses and calculated odds ratios with 95% confidence intervals. The Assessment Group also presented trial data for individual trials, including the hazard ratios taken from the original trials where relevant, and in some instances using the individual trial data to calculate trialspecific odds ratios.

## Change in pacing mode
People in the parallel group trials were randomised to receive a single or dualchamber device. During the trial, some participants changed pacing mode from the one to which they were randomised. Some people randomised to the dualchamber pacemaker device arm changed to singlechamber atrial or singlechamber ventricular mode. Some people randomised to the singlechamber atrial pacemaker device arm changed to a dualchamber pacemaker device (if they developed atrioventricular block) or a singlechamber ventricular device (if they developed atrial fibrillation). A metaanalysis of all 3 parallel group trials comparing 857 people randomised to dualchamber pacemaker devices with 785 people randomised to singlechamber atrial pacemaker devices, reported that statistically significantly fewer people with a dualchamber pacemaker changed pacing mode than those in the singlechamber pacemaker group (odds ratio  0.50, 95% confidence interval  0.37 to 0.67). Most people who changed from a singlechamber atrial pacemaker changed to a dualchamber pacemaker, primarily because of the development of high degree atrioventricular block, or Wenckebach block during implantation. However, there were also a small number of people who switched from singlechamber atrial pacing to singlechamber ventricular pacing, primarily because of persistent atrial fibrillation. The Assessment Group noted that in DANPACE, the results for change in pacing mode and reoperation were probably conservative because the incidence of atrioventricular block leading to these outcomes would have continued to increase over time beyond the followup period of the trial.

## Atrial and ventricular pacing
The proportion of atrial and ventricular pacing varied greatly between the studies, study arms and pacing mode, which may have been associated with differences in the level of atrial fibrillation across the trials. In the parallel trials, dualchamber devices were associated with between 57% and 67% atrial pacing, and ventricular pacing between 17% and 90%. For singlechamber devices, the rate of atrial pacing ranged from 53% to 69%, and ventricular pacing ranged from 3% to 99% (Albertsen et al. , for those who had upgraded from single to dual). In the crossover trials, the rate of dualchamber atrial pacing was only reported by Schwaab et al. (2001; 95%), and the rate of ventricular pacing was reported by Lau et al. (1994; 64%) and Schwaab et al. (99%). For singlechamber devices, the rate of atrial pacing was not reported, and the rate of ventricular pacing was only reported by Schwaab et al. (95%). The Assessment Group noted that although the dualchamber pacemakers in DANPACE (2011) were programmed in a way intended to reduce unnecessary ventricular pacing, ventricular pacing was still 65% (with a range of 33%), which may have offset some of the benefit of implanting a dualchamber pacemaker.

## Allcause mortality
Allcause mortality was reported in DANPACE (2011) and Nielsen et al. (2003), and for both studies there were no statistically significant results. DANPACE (for which the primary outcome was allcause mortality) had an unadjusted hazard ratio for single compared with dualchamber pacemakers of 1.06 (95% CI 0.88 to 1.29), an adjusted (for patient characteristics) hazard ratio of 0.94 (95% CI 0.77 to 1.14), and there were no statistically significant results in any of the predefined subgroups (age, gender, hypertension, left ventricular ejection fraction, history of atrial fibrillation, previous myocardial infarction, PQ interval, diabetes, NYHA classification; p>0.45). For Nielsen et al., the Assessment Group derived an odds ratio from the trial for dual compared with singlechamber pacemakers of 1.47 (0.64 to 3.38). In a metaanalysis of both trials (DANPACE and Nielsen et al.), there was no statistically significant difference in allcause mortality between dual (n=831) and singlechamber atrial (n=761) pacemakers (OR 0.97, 95% CI 0.67 to 1.41).

## Heart failure
The outcome measures used as a proxy for heart failure varied between the 3 parallel studies, including:
NYHA class at end of followup
number of people taking diuretics
heart failure leading to hospitalisation
number of cases of new heart failure, defined as new NYHA class IV or if 2 or more of the following indicators were present:
presence of oedema
presence of dyspnoea
NYHA class III
number of people with an increase in consumption of diuretics
number of people with an increase in at least 1 NYHA class.
There was no statistically significant difference between dual and single atrial pacing for the outcome of heart failure. DANPACE (2011) conducted predefined subgroup analyses for single compared with dualchamber pacemakers for a younger (75 years or under) and older (over 75 years) population, which showed that in younger people, those with a singlechamber pacemaker were at a statistically significantly lower risk of developing heart failure than those with dualchamber pacemakers (hazard ratio  0.72, 95% CI 0.53 to 1.00, p=0.05), whereas in the older subgroup, those with singlechamber pacemakers were at a statistically significantly higher risk than those with dualchamber pacemakers (HR 1.34, 95% CI 1.01 to 1.80, p=0.05). All other subgroup analyses were nonsignificant (p>0.31).

## Atrial fibrillation
DANPACE (2011) and Nielsen et al. (2003) reported results on the incidence of atrial fibrillation, diagnosed by standard 12lead electrocardiogram (ECG) at planned followup visits. In DANPACE, atrial fibrillation was defined as either paroxysmal (the first diagnosis of atrial fibrillation detected in the ECG and verified by the pacemaker telemetry at a planned followup visit) or chronic (atrial fibrillation at 2 consecutive followup visits and at all subsequent followup visits). DANPACE showed that the risk of paroxysmal atrial fibrillation was statistically significantly lower for dual compared with singlechamber pacemakers (OR 0.75, 95% CI 0.59 to 0.96), although there was no statistically significant difference for chronic atrial fibrillation (OR 0.96, 95% CI 0.68 to 1.33). In addition, subgroup analyses of paroxysmal atrial fibrillation in DANPACE showed that dualchamber pacing was associated with statistically significantly lower paroxysmal atrial fibrillation in subgroups of people without a prior history of atrial fibrillation, higher BMI, and a dilated left atrium at baseline (p<0.05). The Assessment Group noted that Nielsen et al. reported conflicting results: that the risk of developing atrial fibrillation (paroxysmal and chronic combined) was statistically significantly higher for dual compared with singlechamber pacemakers (OR 3.19, 95% CI 1.05 to 9.67).The Assessment Group noted that both DANPACE and Nielsen were goodquality trials but stated that, because DANPACE was the larger trial (almost 10 times the size of Nielsen et al.) and had a longer mean followup, it was reasonable to have more confidence in the results of DANPACE.

## Stroke
DANPACE (2011) and Nielsen et al. (2003) reported the effectiveness of single compared with dualchamber pacemakers for stroke. DANPACE reported a nonstatistically significant unadjusted hazard ratio for stroke of 1.13 (95% CI 0.72 to 1.80, p=0.59) for people with single atrial pacing compared with dual pacing, and an adjusted (for patient characteristics) hazard ratio of 1.11 (95% CI 0.70 to 1.77, p=0.65). The results of the Nielsen et al. study were also not statistically significant (p=0.32). A metaanalysis of both studies reported no statistically significant difference between dual and singlechamber pacemaker devices for stroke (OR 0.93, 95% CI 0.60 to 1.45).

## Exercise capacity
Exercise capacity was reported in the parallel trial Albertsen et al. (2008) and in the crossover trials Gallick et al. (1994) and Schwaab et al. (2001). Albertsen et al. reported that at 12 months' followup: people with a single atrial pacemaker walked statistically significantly further than patients with a dualchamber pacemaker (p<0.05) based on the 6minute walking test to assess either exercise tolerance, capacity or both, measuring the distance a person is able to walk over a total of 6 minutes on a hard, flat surface. However, the Assessment Group noted significant uncertainty in this result, which almost did not reach the clinically important difference of 5480 metres, and that no statistical significance had been demonstrated at baseline. Schwaab et al. reported a statistically significantly better exercise capacity with single atrial pacing mode compared with dual pacing mode, for bicycle exercise duration and workload (p<0.05). Gallick et al. reported no statistically significant difference between the pacing modes when using the upright bicycle exercise to test exercise capacity (p=0.74) The Assessment Group noted that Gallick et al. was a very shortterm study, with both pacing modes tested in the same day with 0.5 to 1 hour rest in between, which may partly explain the difference in the result from Schwaab et al.

## Further surgery
The need for pacemaker reoperation during followup was an outcome in DANPACE (2011), in which there were statistically significantly more participants in the singlechamber pacemaker arm needing a reoperation compared with the dualchamber pacemaker arm (unadjusted HR 1.99, 95% CI 1.53 to 2.59; adjusted  HR 2.00, 95% CI 1.54 to 2.61). The only statistically significant difference in reason for reoperation was need for surgical change of mode of pacing (dual n=4, single n=66, p<0.001), primarilyfrom single to dualchamber pacemaker because of the development of highgrade atrioventricular block.

## Adverse effects of pacemaker implantation
Only Albertsen et al. (2008) and DANPACE (2011) reported data on adverse effects linked to pacemaker implantation. Albertsen et al. considered complications around device implantation and did not report any adverse events in either dual or singlechamber atrial pacemakers. DANPACE did not report adverse effects at implantation, but did consider the indications for reoperation during followup. Of 1415 patients in both arms, 240 had 1 or more reoperations during the followup period. The more frequent indications for reoperation were battery depletion (dual n=42, single n=59), lead complications (dual n=30, single n=37) and need for change of pacing mode (dual n=4, single n=66). Less common indications for reoperation were surgical or mechanical complications (dual n=7, single n=10), infection (dual n=3, single n=3), skin erosion (dual n=3, single n=1) or device failure (dual n=2, single n=2). The only indication that was statistically significantly different between the dual and single atrial pacemaker arm was surgical change in pacing mode.

## Healthrelated quality of life
Quality of life was studied in the crossover trials Lau et al. (1994) and Schwaab et al. (2001). Lau et al. used the Visual Analogue Scale (VAS) for general wellbeing, the Specific Activity Scale (SAS) functional questionnaire, 12item General Health Questionnaire (GHQ; a measure of current mental health), symptom questionnaire and Somatic Symptoms Inventory (SSI) adapted for local use from the Bradford Somatic Inventory (which assessed adequacy of daily life activities, emotional adjustment, social interactions , work adjustment, sleep, fatigue and appetite). Schwaab et al. used 3 different selfadministered questionnaires relevant to this appraisal: the VAS for general wellbeing, VAS Karolinska questionnaire (contains 16 questions on cardiovascular symptoms relevant to pacemaker patients) and SAS functional questionnaire. The Assessment Group noted that results for both general wellbeing and functional status were similar across Lau et al. and Schwaab et al., with no statistically significant difference between dual or singlechamber pacing modes in either trial. For multidimensional measures, there was no statistically significant difference between the pacing modes for tests of mental wellbeing (12GHQ, SSI), or for most symptoms in either Lau et al. or Schwaab et al. Schwaab et al. reported people experiencing less dizziness on single atrial pacing than dualchamber pacing (p<0.05); however, Lau et al. did not find a difference for the same symptom. Schwaab et al. was the only included trial that used the multidimensional qualityoflife questionnaires (selfperceived health status) with a section on cognitive function and reported no statistically significant difference between single atrial and dual pacing modes. The Assessment Group noted that there was a substantial amount of uncertainty around all qualityoflife results, because both trials were relatively small and had limited followup.

# Cost effectiveness
The Assessment Group carried out a systematic review of existing costeffectiveness evidence and identified 12 papers for inclusion in its review. It provided a narrative summary of the included studies; however, it stated that it had not been able to identify any UKbased economic evaluations addressing the population in the scope (that is, dualchamber compared with singlechamber atrial pacemakers for people with symptomatic bradycardia caused by sick sinus syndrome and no evidence of atrioventricular block) since the publication of TA88. Therefore, the Assessment Group developed an independent economic model. No other submissions or economic models were provided by the companies as part of this appraisal.

## Identified economic evaluations
The Assessment Group identified 12 papers of relevance in its systematic literature review, which included 2 costutility analyses that were relevant to the population in this appraisal: 1 NHSbased (Castelnuovo et al. , developed for TA88) and 1 nonNHSbased (Oddershede et al. , partly based on DANPACE 2011). Castelnuovo et al. compared dual with singlechamber (atrial or ventricular) pacemakers over a 10year time horizon for several subpopulations with bradycardia. The Castelnuovo paper found singlechamber atrial pacemakers to dominate (that is, were more effective and less costly than) dualchamber pacemakers for sick sinus syndrome. Oddershede et al. considered (from a Danish healthcare perspective) the costutility of dual compared with singlechamber atrial pacemakers in people with sick sinus syndrome and no atrioventricular block. Depending on the risk stratification, adjustment, and pooling of data used, the cost effectiveness of dual compared with singlechamber atrial pacemakers (assessed by calculating net monetary benefit) ranged from 460 to 7847 when assuming a maximum acceptable incremental costeffectiveness ratio (ICER) of 20,000 per qualityadjusted life year (QALY) gained, and 1238 to 10,615 when assuming a maximum acceptable ICER of 30,000 per QALY gained.

## Model overview
The Assessment Group constructed a Markov cohort model to estimate the cost effectiveness of rateresponsive dualchamber pacemakers compared with rateresponsive singlechamber atrial pacemakers in people with symptomatic bradycardia as a result of sick sinus syndrome without atrioventricular block. The Assessment Group conducted the economic analysis from the perspective of the NHS and Personal Social Services, and the model had a cycle length of 1 month. Costs and health effects were discounted at an annual rate of 3.5%.

## Model structure
The model developed by the Assessment Group contained multiple health states. Patients entered the model in the 'requiring a pacemaker' health state, and then transitioned into either the 'with dualchamber pacemaker' or 'with singlechamber atrial pacemaker' health state. In each arm, patients could then experience adverse events and move on to the 'atrial fibrillation', 'stroke' or 'heart failure' health states. In the singlechamber pacemaker arm only, patients could move on to the 'atrioventricular block' health state, and from there transition to the 'with dualchamber pacemaker (after reoperation)' health state. The Assessment Group noted that all reoperations were assumed to occur in the singlechamber atrial arm only (because the need to change pacing mode to dualchamber pacing was the only reason for reoperation with a statistically significant difference between the 2 arms ), and all reoperations after the atrioventricular block health state were assumed to be an upgrade to a dualchamber pacemaker. Only 1 instance of reoperation was permitted in the model. Patients who moved to the 'heart failure' and 'stroke' health states from the singlechamber arm could have a reoperation; however, they only incurred the costs of reoperation, and remained in the 'heart failure' or 'stroke' health state. In the atrial fibrillation health state, modelled patients could need reprogramming of the device to act as a ventricular pacemaker in the dualchamber arm, or reoperation in the single atrial arm to a singlechamber ventricular device. However, in both arms, patients could transition from 'atrial fibrillation' to 'heart failure' or 'stroke'. Patients were at risk of death in each health state.
The Assessment Group populated the model with a cohort that had the same baseline characteristics of the DANPACE (2011) trial: baseline age was 73 years, and 65% of participants were female. However, rather than using the prevalence of comorbidities from the DANPACE trial of atrial fibrillation (44%), stroke (8%) and heart failure (12%), these were assumed to be zero for all patients on entry to the model. The Assessment Group stated that this assumption was made to simplify the model.

## Modelled treatment effectiveness
The treatment effect for dual compared with singlechamber pacemakers was predominantly informed by results from the DANPACE (2011) trial only. The Assessment Group stated that it did not combine the available trial data because of heterogeneity between the trials as a result of different patient populations (for example, prior history of atrial fibrillation) and different device programming used (for example, different proportions of ventricular pacing). For the risk of heart failure and stroke for people with atrial fibrillation, the Assessment Group carried out targeted literature searches.
Reoperation: Reoperation was assumed to only occur in the singlechamber arm of the model (see section 4.25). All reoperations following the development of atrioventricular block were assumed to be an upgrade to a dualchamber pacemaker. For people with singlechamber atrial devices, the need to change pacing mode was predominantly a result of the development of atrioventricular block needing upgrade to a dualchamber device (see sections 4.12 and 4.19). Therefore, the Assessment Group used the difference in event rates for reoperations between the single and the dualchamber arms in DANPACE (2011) that were because of a need for surgical change of pacing mode to estimate the risk of people in the singlechamber atrial arm developing atrioventricular block per patient per month, and applied this as a constant risk for the lifetime of the model. Because the KaplanMeier plot suggested a nonlinear relationship, reoperation as a timedependent parameter (rather than assuming constant risk) was used in sensitivity analyses. To derive the transition probabilities for the model, the Assessment Group converted the difference in monthly event rates into a monthly probability of atrioventricular block for those with singlechamber pacemakers, generating a value of 0.142. People with singlechamber pacemakers in the stroke or heart failure health states could develop atrioventricular block at the same monthly rate as those not in the heart failure or stroke health states (0.142), and have a reoperation to receive a dualchamber pacemaker. However, they remained in the stroke or heart failure health states, incurring the cost of reoperation but no change in utility. Reoperation was also possible for some people in the singlechamber atrial arm who developed atrial fibrillation and still needed pacing, where onethird of modelled patients had a reoperation to surgically change pacing mode and receive a singlechamber ventricular pacemaker. However, these patients remained in the atrial fibrillation health state and only incurred the costs of the health state with no change in utility.The Assessment Group assumed that at 96 months' postimplantation, based on an 8year battery life, all patients who had not yet experienced reoperation or developed atrial fibrillation received a replacement of their existing pacemaker.
Atrial fibrillation, heart failure and stroke (all patients): For the dualchamber pacemaker arm, the Assessment Group derived event rates for atrial fibrillation, heart failure and stroke from DANPACE (2011) and Riahi et al. (2012) (summary statistics from DANPACE). For the singlechamber arm, the Assessment Group derived event rates for atrial fibrillation, heart failure and stroke by taking the relevant hazard ratios from DANPACE and Riahi et al. and applying these to the associated event rates derived for the dualchamber arm. The Assessment Group then transformed the event rates into monthly probabilities. The following monthly probabilities were used in the model: paroxysmal atrial fibrillation (dual 0.4%, single 0.5%), chronic atrial fibrillation (dual and single 0.18%), heart failure (dual 0.42%; single 0.46%) and stroke (dual and single 0.08%).
Heart failure and stroke (those with atrial fibrillation): The Assessment Group carried out targeted literature searches to estimate the increased risk of heart failure or stroke for those who also have atrial fibrillation. For heart failure, the Assessment Group did not identify any studies; therefore, it assumed in the model that the risk of heart failure was the same in people with and without atrial fibrillation. For stroke, the Assessment Group identified a paper by Gallagher et al. (2014), which reported the results of a populationbased cohort study of people with atrial fibrillation. Gallagher et al. presented incidence rates of stroke, adjusted for covariates such as risk of stroke, age and smoking status for various scenarios of warfarin therapy (currently exposed, recently exposed, history of exposure or no history of exposure). The Assessment Group considered the incidence rate of stroke in people currently exposed to warfarin therapy (0.9 per 100 person years) the most suitable to inform the risk of stroke in people with atrial fibrillation, because current guidelines recommend effective anticoagulation therapy for stroke prevention in people with paroxysmal and persistent atrial fibrillation. The Assessment Group noted this was similar to the monthly rate for those without atrial fibrillation.
Mortality: The Assessment Group assumed (based on pooled estimates of allcause and cardiovascular mortality identified in the clinical literature review) that the risk of death was consistent across all treatment arms, but varied by age and health state. People in the 'with pacemaker' health states had the same risk of death as the age and gendermatched UK general population (because the Assessment Group found no evidence of higher mortality risks for people needing or already implanted with a pacemaker ). The Assessment Group considered 2 overarching forms of mortality in the model: case fatality and allcause mortality:
Case fatality:
               Death directly from the health state experienced. For stroke (with and without atrial fibrillation), the Assessment Group used data presented by Carter et al. (2007), which reported the number of people dying within 30 days of an acute stroke event (n=32/545) and, of these, the number with atrial fibrillation (n=14). People with atrial fibrillation had a probability of stroke of 13.59%, and those without atrial fibrillation had a probability of stroke of 4.07%. For case fatality after heart failure for those without atrial fibrillation, the Assessment Group used Cowie et al. (2000), a populationbased observational study (UK) of patients with a new diagnosis of heart failure, in which 81% of patients were alive 1 month after developing heart failure (therefore the Assessment Group assumed 19% of people with atrial fibrillation died after heart failure). For those with atrial fibrillation, the Assessment Group used a study by Mosterd et al. (2001, Rotterdam), which included prognostic analyses of a populationbased cohort study. Mortality from heart failure in people with atrial fibrillation was associated with a hazard ratio of 2.08 compared with those with heart failure and no atrial fibrillation. The Assessment Group applied this hazard ratio to the probability of death without atrial fibrillation (19%), which generated a probability of death of 34.8%. No case fatality was applied to people with atrial fibrillation alone, as this was found to be nonsignificant in those older than 60 years in Miyasaka et al. (2007) (a 21year communitybased study analysing the allcause mortality risk of people with atrial fibrillation compared with an age and gendermatched general population).
Allcause mortality:
               In addition to death directly from the health state experienced, people within the health states of atrial fibrillation, stroke or heart failure were assumed to be at a generally increased risk of death when compared with the UK general population. Those with atrial fibrillation who also had either stroke or heart failure were assumed to be at further risk of death. The Assessment Group searched the literature for evidence of this increased risk, identifying studies by Pocock et al. (2006) (an analysis of data from the CHARM  programme), Miyasaka et al. and Carter et al. The Assessment Group applied hazard ratios derived from these studies to the risk of death for the age and gendermatched general population to represent the increased risk of death for heart failure (HR 1.32, taken from Pocock et al.), stroke (3.59 for males, 3.14 for females, taken from Carter et al.), and atrial fibrillation (HR 2.08, taken from Miyasaka et al.). For allcause mortality for people with atrial fibrillation and heart failure or stroke, the Assessment Group applied hazard ratios derived from these studies to the risk of death for those with stroke or heart failure without atrial fibrillation. The hazard ratio for stroke and atrial fibrillation was 1.33 (Carter et al.), and the hazard ratio for heart failure and atrial fibrillation was 1.11 (Pocock et al.).
Adverse events: The Assessment Group did not incorporate the effect of adverse events into the model because it did not identify any statistically significant differences in adverse events in the literature other than adverse events leading to reoperation.
Healthrelated quality of life: The Assessment Group carried out a systematic review to identify healthrelated qualityoflife evidence, identifying 6 relevant studies reporting generic, preferencebased measures of quality of life. The Assessment Group noted that all of the healthrelated qualityoflife studies identified for inclusion reported time tradeoff utility data collected directly from patients and, of these, 5 (Fleischmann et al. 2006; Fleischmann et al. 2009; Shulka et al. 2005; Link et al. 2004 and Lamas et al. 2002) reported the results of qualityoflife analyses carried out with the MOST clinical trial, and 1 (LopezJimenez et al. 2002) from the PASE trial. The MOST trial was a UKbased randomised controlled trial comparing 2010 people with sick sinus syndrome who were randomised to either dual or singlechamber ventricular pacing. PASE was a randomised controlled trial of 407 people comparing dual with singlechamber ventricular pacing for people with bradycardia, with a primary end point of healthrelated quality of life. In both trials, patients received dualchamber pacemakers before randomisation to either dual or singlechamber ventricular mode. In addition to the identified utility studies, the Assessment Group carried out a targeted literature search for utility associated with stroke (with or without atrial fibrillation), identifying a study by LuengoFernandez et al. (2013), which evaluated quality of life after transient ischaemic attack and stroke. People in the dual and single 'requiring pacemaker' health states were assumed to have a utility of 0.725 and those in the dual and single 'with pacemaker' health states had a utility of 0.825 (both utilities taken from Fleischmann et al. , which considered the impact of pacemaker device and mode on quality of life). People in the 'atrial fibrillation' health state had a utility of 0.805 (Fleischmann et al. , which considered the impact of atrial fibrillation on quality of life and functional status after implantation). 'Stroke' (with or without atrial fibrillation) was associated with a utility of 0.64 in month 1 and 0.70 thereafter (LuengoFernandez et al. ,). 'Heart failure' (with or without atrial fibrillation) was associated with a utility of 0.64 (taken from LopezJimenez et al. , which described the results of the PASE study). Death was assumed to be associated with a utility of 0.

## Costs
The Assessment Group identified studies for UKspecific resource use and costing studies of atrial fibrillation, heart failure and stroke from the following sources:
Townsend et al. (2012): British Heart Foundation  statistics on coronary heart disease.
LuengoFernandez et al. (2012): a populationbased cohort study of hospitalisation resource use and costs before and after stroke and transient ischemic attack.
LuengoFernandez et al. (2013): a populationbased study of acute and longterm care costs after stroke in people with atrial fibrillation.
In addition, the resource use and costs were based on standard UK sources (NHS reference costs 2012/13, Electronic market information tool  or British national formulary ) for the unit costs applied within the Assessment Group economic model.
Device and implantation costs: The Assessment Group obtained procedure costs (including hardware costs) associated with implantation of a single (1875) or dualchamber (2438) device from a weighted average of episode costs associated with relevant Healthcare Resource Group (HRG) codes (NHS reference costs 2012/13). The Assessment Group assumed that upgrade procedures cost the same as an initial implantation of a dualchamber device. In sensitivity analyses, the Assessment Group used spell level (rather than episode level) data for each HRG code. The Assessment Group assumed that at 96 months' postimplantation, all patients who had not yet experienced reoperation or developed atrial fibrillation received a replacement dualchamber device.
Monitoring costs: Modelled patients received followup checks from a cardiologist (86) after pacemaker implantation, for which the Assessment Group used HRG codes. Based on expert clinical opinion, the Assessment Group assumed initial followup to be 1 week after implantation, and a second followup at 2 months postimplantation and subsequent annual visits. Therefore, the Assessment Group applied the cost of a followup visit on entry into the dual and single 'requiring pacemaker' and 'with pacemaker' health states. The cost of a followup visit was also applied annually to all patients in the dual and single 'with pacemaker' health states.
Episode costs: Modelled patients were exposed to the risk of heart failure and stroke, with or without the presence of atrial fibrillation:
If atrial fibrillation was absent, the Assessment Group used a weighted average of episode level costs associated with relevant HRG codes for the occurrence of heart failure (1228) or stroke (1427).
If atrial fibrillation was present, the episode cost of stroke (11,275) was based on the populationbased cohort study reported by LuengoFernandez et al. (2013). The Assessment Group found no evidence indicating that the episode cost of heart failure would differ in the presence of atrial fibrillation.
The Assessment Group applied the episode cost of heart failure to people entering the 'heart failure' and 'atrial fibrillation and heart failure' health states. The Assessment Group applied the episode cost of stroke to people entering the 'stroke' health state, and the episode cost of stroke after atrial fibrillation to people entering the 'atrial fibrillation and stroke' health state. If people developed atrial fibrillation and needed their device reprogramming to ventricular mode, they accrued the following costs:
People with a dualchamber device: modelled patients accrued the costs of a consultation with a cardiologist (86) and an ECG (41), based on HRG codes.
People with a singlechamber atrial device: modelled patients accrued the cost of a replacement single ventricular device (the Assessment Group assumed an equivalent cost to the single atrial pacemaker of 1875).
The Assessment Group applied (based on expert clinical opinion) the cost of reprogramming and device replacement to onethird of people developing atrial fibrillation. The impact of this assumption was tested in a sensitivity analysis.
Longterm costs: After the onset of heart failure, stroke or atrial fibrillation, the Assessment Group assumed modelled patients accrued costs over the long term, for example, medication, hospitalisation and primary care costs.
Heart failure:
               the Assessment Group used national prevalence and cost statistics reported in the 2012 British Heart Foundation coronary heart disease statistics publication, calculating the relative prevalence of heart failure as a percentage of cardiovascular disease, and estimating the 2011 UK direct healthcare costs of cardiovascular disease and heart failure, resulting in annual costs of 3316 per person. The Assessment Group applied this cost monthly (276 per cycle) to people in the 'heart failure' and 'atrial fibrillation and heart failure' health states.
Stroke:
               the Assessment Group used the cost of hospitalisation (1564 stroke alone, and 3649 for atrial fibrillation and stroke) estimated from a populationbased cohort study reported by LuengoFernandez et al. (2012) and the cost of medication (81) and primary care (31) for stroke derived from Townsend et al. (2012). The Assessment Group applied the costs monthly to people residing in the 'stroke' (140 per cycle) and 'atrial fibrillation and stroke' (400 per cycle) health states.
Atrial fibrillation:
               the Assessment Group identified longterm costs of 955 per person per year for primary care and hospitalisation from a predictive study carried out by Stewart et al. (2004) (which evaluated the UK health and social services cost of atrial fibrillation in 1995, and projected costs to 2000 based on epidemiological trends). The Assessment Group also assumed that people with atrial fibrillation received effective anticoagulation therapy (6.45 per cycle) with apixaban, dabigatran etexilate, rivaroxaban or warfarin in addition to the costs of primary and hospital care (because the Assessment Group stated this reflected current clinical guidance). The Assessment Group applied the costs of primary care, hospitalisation and anticoagulation as a cost per cycle of 86.01. The Assessment Group noted that it used current market shares for anticoagulation in the base case, but that these may be subject to change over time; therefore, it used additional scenarios in sensitivity analyses. The longterm costs were applied monthly to people residing in the 'atrial fibrillation', 'atrial fibrillation and stroke' and 'atrial fibrillation and heart failure' health states.

## Results of the economic analyses
After consultation on the Assessment Group report, an error was noted in the calculation of total UK direct costs of cardiovascular disease, which had been underestimated in both arms of the model. This reduced the basecase ICER, and all ICERs in scenario and sensitivity analyses. The original basecase ICERs are described in detail in the overview and an Erratum has been produced to describe the corrections, both of which are available in the committee papers. This document contains only the corrected ICERs.
The deterministic basecase ICER for dual compared with singlechamber atrial pacemakers was 6056 per QALY gained (incremental costs 269, incremental QALYs 0.04), and the mean probabilistic ICER across 1000 simulations was 6068 per QALY gained (incremental costs 277, incremental QALYs 0.05). The probability of dualchamber pacemakers being cost effective at a maximum acceptable ICER of 20,000 per QALY gained was 72.9%, and at 30,000 per QALY gained was 78.7%. The Assessment Group noted that in 66% of simulations, dualchamber devices had both greater costs and greater QALYs than single atrial pacemakers, and in 24.1% of simulations dualchamber pacemakers dominated singlechamber atrial pacemakers (that is, produced more QALYs at a lower cost). Singlechamber devices dominated dualchamber devices in 9% of cases.
The Assessment Group carried out oneway sensitivity analyses on the following parameters by using the lower and upper limits of the 95% confidence intervals: age, efficacy values, utility values, costs, allcause mortality and heart failure hospitalisation. The Assessment Group presented a tornado diagram of the 10 most influential results in the deterministic sensitivity analysis, which showed the variance from the base case, and noted that many of the parameters tested had minimal impact on the deterministic costeffectiveness results. The Assessment Group noted that the parameters most likely to increase the deterministic ICER over 20,000 per QALY gained were:
highest cost of implant or procedure cost for dualchamber pacemaker (23,010 per QALY gained)
lowest cost of implant or procedure cost for singleatrial pacemaker (27,409 per QALY gained)
lowest risk of heart failure (singlechamber atrial pacemakers dominated dual; the Assessment Group noted that this result was driven by an increase in cost of 710 and a modest reduction in benefit (0.01).
The Assessment Group conducted structural sensitivity analyses. When using a 5year time horizon, the deterministic ICER was 14,261 per QALY gained, and the probabilistic ICER was 13,837 per QALY gained. When using KaplanMeier data as the basis for reoperation, the ICER was 3425 per QALY gained.
The Assessment Group conducted scenario analyses on the basecase results, including varying efficacy sources, cost estimates (using spell costs of pacemaker device and implantation ), discount rates and differing risk of developing heart failure by age. Most of the scenarios explored had a minor impact on the resulting ICER with the exception of:
assuming no difference in risk of developing heart failure (22,213 per QALY gained)
reprogramming or device replacement for atrial fibrillation in 0% patients (10,872 per QALY gained)
reprogramming or device replacement for atrial fibrillation in 100% patients (dualchamber pacemakers dominated single atrial)
A cumulative ICER for all 'worstcase' scenarios that combined several assumptions taken from efficacy and cost scenarios that increased the ICER from the base case (monthly cost of heart failure from TA88, the risk of stroke from the metaanalysis conducted by the Assessment Group, spell level costs of implantation, reprogramming or device replacement for atrial fibrillation of 0%, and assuming no difference in risk of developing heart failure between the 2 types of implant) (48,738 per QALY gained).
To address the uncertainty in the appraisal arising from the lack of a specific list price for pacemaker devices, the Assessment Group conducted a threshold analysis, in which the costs of dualchamber pacemakers were increased until the ICER reached 20,000 per QALY gained. When the price of dualchamber pacemakers was increased by 495 to 2933 (and the price of singlechamber atrial pacemakers remained at 1875), the ICER was 19,992 per QALY gained (incremental costs 888.28, incremental QALYs 0.04).

# Consideration of the evidence
The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of dualchamber pacemakers, having considered evidence on the nature of symptomatic bradycardia due to sick sinus syndrome and no evidence of atrioventricular block, and the value placed on the benefits of dualchamber pacemakers by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources.
The Committee considered the experience of people with bradycardia due to sick sinus syndrome and no evidence of atrioventricular block. It noted that the patient expert's personal statement outlined that before pacemaker implantation, initially the cause of ill health was unclear with nonspecific symptoms such as tiredness, nausea and lightheadedness, later followed by sickness, diarrhoea, exhaustion and fainting. The Committee further noted that for the patient expert, the implantation of a dualchamber pacemaker led to an improved and more stable quality of life. The Committee heard from the clinical experts that a dualchamber pacemaker can be programmed to be used as a singlechamber pacemaker, and that the likelihood of reoperation to upgrade from a singlechamber atrial pacemaker to a dualchamber pacemaker because of the development of atrioventricular block was an important consideration for patients. The Committee recognised that implantation of a pacemaker device was the only effective treatment for people with this condition, and the risk of reoperation was an important consideration in its deliberations.
The Committee considered the treatment pathway for people with symptomatic bradycardia due to sick sinus syndrome without evidence of atrioventricular block. It noted that TA88 had originally recommended singlechamber atrial pacemakers for treatment of the disease, however it heard from clinical experts that clinical practice had changed since publication of the guidance. Clinical experts noted that in 2012, implantation of a singlechamber atrial pacemaker for any heart condition was rare (of around 40,000 pacemaker implants in the UK, around 165 were singlechamber atrial devices). For pure sinus node disease, dualchamber devices were now usually implanted because the DANPACE trial had demonstrated a statistically significant reduction with dualchamber pacemakers in the need for reoperation to surgically change pacing mode, which would be needed following the development of atrioventricular block. The Committee further heard from the clinical experts that most of the pacemaker devices implanted are rate responsive. The Committee concluded that in clinical practice, the pacemaker devices implanted were by default rate responsive, and that dualchamber rather than singlechamber atrial devices were already being implanted for most patients with the condition.

# Clinical effectiveness
The Committee considered the quality of the evidence comparing dual with singlechamber atrial pacemakers for people with sick sinus syndrome and no evidence of atrioventricular block. It noted that, although the crossover trials were small and had limited followup, the parallel trials were larger, and in particular DANPACE (2011) was a large, highquality trial, which provided the best available evidence base for this appraisal. It heard from the clinical experts that, because randomisation was assigned before the pacemaker was implanted in the DANPACE trial, approximately 6.5% of those randomised to receive a singlechamber atrial device had instead received a dualchamber device because it was more clinically suitable at the time of the intervention. The clinical experts stated that because the estimates of clinical efficacy were based on an intentiontotreat analysis, the likely impact of this was to underestimate the efficacy of dualchamber devices. The Committee concluded that it was satisfied with the quality of the clinical evidence outlined in this appraisal, and that DANPACE and the other trials could be used as a basis for its decisionmaking.
The Committee considered the clinicaleffectiveness evidence for dual compared with singlechamber atrial pacemakers for the population in this appraisal. It noted that the clinical evidence indicated that there were no statistically significant differences shown for the whole population for several important outcomes, including mortality, stroke, quality of life and heart failure. However, it noted that dualchamber pacemakers were associated with a statistically significant reduction in paroxysmal atrial fibrillation, the need to change pacing mode and reoperation. It heard from the clinical experts that, whereas generally there were no differences in a number of clinical outcomes such as mortality, the key reason for preferring a dualchamber device was a reduced need for reoperation. The Committee concluded that, although there were no statistically significant differences for a number of important outcomes, dualchamber pacemakers had been clearly demonstrated to statistically significantly reduce the need for reoperation.
The Committee considered the importance of reoperation as an outcome for the population in this appraisal. It heard from the clinical experts that if a single atrial pacemaker is implanted in people with sinus node disease without atrioventricular block, some will need reoperation because of the development of atrioventricular block. However, there was no reliable way to predict who would be affected. The clinical experts stated complications occurred in up to 20% of reoperations, and the risks associated with reoperation should not be underestimated, because they could be unpleasant and severe. This was particularly the case if the subclavian vein had become occluded (that is, the vein used during the placement of pacemaker leads had become blocked), which would make it difficult to explant the existing leads and implant the new leads needed for a dualchamber pacemaker. The Committee concluded that the reduced need for reoperation was a significant benefit for patients of dualchamber pacemakers.
The Committee discussed the importance of the degree of ventricular pacing as an outcome for the population in this appraisal. It heard from the clinical experts that in DANPACE (2011), ventricular pacing occurred in around 65% of patients, despite using pacemaker algorithms that were designed to minimise ventricular pacing. It heard from the clinical experts about the adverse effects of unnecessary ventricular pacing, which interferes with the timing of the pacing of the upper and lower chambers of the heart, making it beat more or less efficiently. The longterm effects of this were unpredictable and potentially very harmful, possibly leading to additional morbidities and increased risk of mortality. The clinical experts were in agreement that dualchamber pacemakers implanted for the treatment of symptomatic bradycardia as a result of sick sinus syndrome without atrioventricular block should use algorithms that minimise unnecessary ventricular pacing. However, they noted that the dualchamber pacemakers that have come to market since the publication of DANPACE have been developed to reduce the risk of unnecessary ventricular pacing, and a typical dualchamber pacemaker used in clinical practice in England would now be expected to unnecessarily pace only around 10% of ventricular beats. The Committee concluded that although the consequences of unnecessary ventricular pacing could be harmful, the capabilities of modern dualchamber pacemakers had evolved to substantially reduce levels of unnecessary pacing.
The Committee discussed the results of the predefined subgroup analysis in DANPACE (2011) for heart failure, which stratified patients by age. It noted that this analysis demonstrated statistically significant reductions in heart failure with dualchamber pacemakers compared with single atrial pacemakers for people aged over 75, but higher rates of heart failure for those aged under 75. The Committee noted that the results for this subgroup analysis in DANPACE were only marginally statistically significant (for both groups p=0.05) and that the results for the whole population had not shown a statistically significant difference. It heard from the clinical experts that the agestratified result was unexpected and counterintuitive because the risk of heart failure increases with age, and that they could identify no biologically plausible clinical reason that could explain the result. It heard from the clinical experts that the algorithm for dualchamber pacemakers in the DANPACE trial had an unusually long atrioventricular delay (which is also longer than used in dualchamber pacemakers in clinical practice), which is likely to have contributed to a higher rate of ventricular pacing and may have accelerated the onset of heart failure. The clinical experts also noted that since the publication of DANPACE, modern dualchamber devices had further reduced the level of unnecessary ventricular pacing, which had helped to improve heart outcomes for this population. The Committee therefore concluded that it was likely that the results of the agestratified subgroup analysis would not be seen in current clinical practice, particularly with the use of newer pacemakers that reduce levels of ventricular pacing.
The Committee considered whether there were any situations in which it would be more appropriate for a person with sick sinus syndrome and no evidence of atrioventricular block to receive a single atrial rather than a dualchamber pacemaker. It heard from the clinical experts that this would only occur in very rare and more complex circumstances. One example given was for people who were particularly young with isolated sinus node disease (for example, because of surgical sinoatrial node ablation) and less likely to develop atrioventricular block (because the incidence of atrioventricular block is much higher in older people). The clinical experts explained that in these circumstances, the consequences of vein occlusion in 20 or 30 years' time would be a more important consideration for patients than the need for reoperation as a result of atrioventricular block. The Committee acknowledged that there may be rare and complex circumstances in which, for a small minority of patients with isolated sinus node disease who are at particularly low risk of developing atrioventricular block, the risks and benefits on balance would favour implantation of a singlechamber atrial pacemaker. However, it was not aware of any clinical characteristics or data that could be used to robustly identify these populations. The Committee concluded that, for most people with symptomatic bradycardia due to sick sinus syndrome without atrioventricular block, dualchamber pacing was associated with clinical benefits compared with singlechamber atrial pacing.

# Cost effectiveness
The Committee considered the costeffectiveness results generated by the Assessment Group's health economic model. It noted that the estimated probabilistic and deterministic ICERs of approximately 6000 per QALY gained were very low. However, it agreed that there were high levels of uncertainty in these ICERs, as they were not based on the list price of the devices.
The Committee considered the estimated costs of followup with a consultant after pacemaker implantation within the model. It heard from the clinical experts that the costs and frequency of followup for singlechamber atrial pacemakers had been underestimated in the model, because in clinical practice the implantation of a singlechamber atrial device includes electrophysiological testing to assess the integrity of atrioventricular conduction and the Wenckebach phenomenon, which had not been included in the modelled costs of a singlechamber atrial pacemaker. The Committee concluded it was plausible that the costs of singlechamber pacemakers may have been slightly underestimated in the economic model; however, this was unlikely to have a significant impact on the results of the costeffectiveness analysis.
The Committee considered the estimated costs of pacemaker implantation in the model. It was aware that, when costing devices, the Assessment Group had used a weighted average of HRG codes (which included device and procedure costs), rather than using the list price of the technologies as specified in the technology appraisals methods guide. The Committee heard from the Assessment Group that there were a range of devices with different costs associated, and therefore there was not a specific list price for a dual or singlechamber atrial device. It further heard from the Assessment Group, the company and the clinical experts that the HRG codes were the most appropriate source to calculate the realworld price paid by commissioners and healthcare resource utilisation for pacemaker implantation, because they took into account the costs of the whole procedure rather than the device alone. The Committee concluded that although a costeffectiveness analysis based on the list price of pacemakers would have been useful, the use of HRG codes is likely to approximate the realworld costs and resource utilisation of dualchamber pacemaker implantation.
The Committee discussed the extent of uncertainty that had been generated by the lack of specific list price of devices in the model. It noted that the approach taken by the Assessment Group to use a weighted average of costs instead of list prices could potentially disguise the true cost of more expensive devices, for example, dualchamber devices with additional capabilities. However, it heard from the clinical experts that, although some devices were more expensive than others and a small minority of patients did need more expensive devices with more complex algorithms, there was no incentive for clinicians to use unnecessarily expensive dualchamber devices, because the additional pacing algorithms conferred would not be of clinical benefit. The Committee heard from the Assessment Group that in the absence of a single list price, it had conducted an additional exploratory analysis on the impact of device costs on the ICER. This indicated that the price difference between dual and singlechamber atrial pacemakers had to be increased substantially, and to a level unlikely to be seen in clinical practice, before dualchamber pacemakers would not be cost effective at a maximum acceptable ICER of 20,000 per QALY gained (see section 4.44). The Committee was therefore sufficiently reassured by the threshold analysis to conclude that the risk of the ICER increasing to a level that would not be considered costeffective was acceptable for their decisionmaking.
The Committee summarised its discussions and reflected on the most plausible ICER for dual compared with singlechamber atrial pacemakers for people with sick sinus syndrome and no evidence of atrioventricular block. It noted that, in clinical practice, most people were already receiving dualchamber pacemakers, because the results of DANPACE (2011) had demonstrated a reduced need for reoperation. It further noted that this was a significant benefit of dualchamber pacemakers, because reoperation was associated with unpleasant and severe complications affecting up to 20% of people having reoperation. The Committee was persuaded that, although the list price of pacemakers had not been incorporated into the model and instead a weighted average of HRG codes for dual and singlechamber pacemakers had been used, this was acceptable for approximating the costs of the procedures, and the ICERs generated were acceptable for the purpose of decisionmaking. It concluded that the true ICER was likely to be higher than the estimated probabilistic and deterministic ICERs of approximately 6000 per QALY gained, because there is no difference in the effectiveness of dualchamber pacing for outcomes including heart failure, and also because of the higher acquisition cost of dualchamber pacemakers. However, the higher acquisition costs of dualchamber pacemakers were likely to be at least partially offset by a reduced need for reoperation. The Committee was further reassured by the threshold analysis that there was a low risk of the ICER increasing to a level that would not be considered cost effective (see section 4.44) when assuming a maximum acceptable ICER of 20,000 per QALY gained. On balance, the Committee concluded that the clinical effectiveness evidence had demonstrated the clinical superiority of dualchamber devices because of the statisticallysignificantlyreduced need for reoperation (a significant benefit for patients), and that the costeffectiveness evidence had shown that the most plausible ICER was likely to be under 20,000 per QALY gained. Therefore dualchamber pacemakers for symptomatic bradycardia due to sick sinus syndrome with no evidence of atrioventricular block were recommended as a costeffective use of NHS resources.

# Summary of Appraisal Committee's key conclusions
TA324
Appraisal title: Dual-chamber pacemakers for symptomatic bradycardia due to sick sinus syndrome without atrioventricular block (part review of technology appraisal guidance 88)
Section
Key conclusion
Dualchamber pacemakers are recommended as an option for treating symptomatic bradycardia due to sick sinus syndrome without atrioventricular block.
The Committee noted that, in clinical practice, most people were already receiving dualchamber pacemakers, because the DANPACE trial had demonstrated dualchamber pacemakers were associated with a statistically significant reduction in the need for reoperation. It further noted that reoperation was associated with unpleasant and severe complications affecting up to 20% of people having reoperation.
The Committee noted that the basecase incremental costeffectiveness ratio (ICER) of approximately 6000 per qualityadjusted life year (QALY) gained contained high levels of uncertainty and was likely to be higher in clinical practice because there is no difference in the effectiveness of dualchamber pacing for outcomes including heart failure, and also because a list price for devices was not available to use in the model. However the Committee was reassured by the threshold analysis, which indicated that the price difference between dual and singlechamber atrial pacemakers had to be increased substantially, and to a level unlikely to be seen in clinical practice, before dualchamber pacemakers would not be cost effective at a maximum acceptable ICER of 20,000 per QALY gained. The Committee concluded that the most plausible ICER was likely to be under 20,000 per QALY gained.
Current practice
Clinical need of patients, including the availability of alternative treatments
The Committee noted symptoms of the disease include tiredness, nausea, diarrhoea and fainting. It heard from the clinical experts that the likelihood of reoperation to upgrade from a singlechamber atrial pacemaker to a dualchamber pacemaker because of the development of atrioventricular block was an important consideration for patients. The Committee recognised that implantation of a pacemaker device was the only effective treatment for the disease.
The technology
Proposed benefits of the technology
How innovative is the technology in its potential to make a significant and substantial impact on healthrelated benefits?
The Committee concluded that dualchamber pacemakers had been clearly demonstrated to statistically significantly reduce the need for reoperation compared with singlechamber atrial pacemakers.
What is the position of the treatment in the pathway of care for the condition?
In clinical practice dualchamber devices are already being implanted for most of the population covered in this appraisal (because of the reduced need for reoperation as a result of atrioventricular block). The majority of patients' devices are rate responsive.
Adverse reactions
The need for additional leadin dualchamber pacemakers might lead to an increased risk of complications, such as lead displacement, puncture of the lung when placing the leads, and infection of the pacemaker pocket or the leads. Complications arising after pacemaker implantation may include dysfunction of the pacemaker or of the leads, infection or erosion of the pacemaker site or its leads, and the development of pacemaker syndrome, stroke, heart failure or atrial fibrillation. Reoperation may be needed as a result of a complication or endofbattery life.
Evidence for clinical effectiveness
Availability, nature and quality of evidence
There were 6 relevant randomised controlled trials (3 parallel group trials, 3 crossover trials).
The crossover trials were small and had limited followup and the parallel trials were larger, and in particular DANPACE (2011) was a large, highquality trial, which provided the best available evidence base for this appraisal.
Relevance to general clinical practice in the NHS
The Committee was satisfied that DANPACE and the other trials were clinically relevant as a basis for its decisionmaking.
Uncertainties generated by the evidence
The crossover trials were small and had limited followup. Quality of life data was only available from 2 crossover trials.
The Committee noted that the clinical evidence indicated that there were no statistically significant differences shown for the whole population for several important outcomes, including mortality, stroke, quality of life and heart failure.
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?
A subgroup analysis in DANPACE demonstrated statistically significant reductions in heart failure with dualchamber pacemakers compared with single atrial pacemakers for people aged over 75, but higher rates of heart failure for those aged under 75. However the results were only marginally statistically significant (for both groups p=0.05) and clinical experts were of the opinion that there was no biologically plausible reason that could explain the higher risk of heart failure in younger patients. The Committee concluded that it was likely that the results of the subgroup analysis would not be seen in current clinical practice.
The Committee acknowledged that there may be rare and complex circumstances in which the risks and benefits on balance would favour implantation of a singlechamber atrial pacemaker. However, it was not aware of any clinical characteristics or data that could be used to identify these populations.
Estimate of the size of the clinical effectiveness including strength of supporting evidence
The Committee noted that the clinical evidence indicated there were no statistically significant differences shown for the whole population for several important outcomes, including mortality, stroke, quality of life and heart failure. However, it noted that dualchamber pacemakers were associated with a statistically significant reduction in paroxysmal atrial fibrillation, the need to change pacing mode, and reoperation. It heard from the clinical experts that the key reason for preferring a dualchamber device was a reduced need for reoperation.
The Committee noted that, although the crossover trials were small and had limited followup, the parallel trials were larger, and in particular DANPACE (2011) was a large, highquality trial, which provided the best available evidence base for this appraisal. The Committee was satisfied with the quality of the clinical evidence outlined in this appraisal.
For reviews (except rapid reviews): How has the new clinical evidence that has emerged since the original appraisal (TA88) influenced the current recommendations?
Several new trials have been published since the publication of TA88. In particular, DANPACE was a large highquality trial, providing the best evidence base for this appraisal. This indicated that that dualchamber pacemakers were associated with a statistically significant reduction in the need for reoperation compared with singlechamber atrial pacemakers. Clinical experts noted that for pure sinus node disease dualchamber devices were now usually implanted since the publication of DANPACE, because of the possibility of progression to atrioventricular block (needing reoperation).
Evidence for cost effectiveness
Availability and nature of evidence
No submissions or economic models were provided by the companies. The Assessment Group constructed a Markov cohort model from the perspective of the NHS and Personal Social Services. The model had a cycle length of 1 month. Costs and health effects were discounted at an annual rate of 3.5%.
Uncertainties around and plausibility of assumptions and inputs in the economic model
When costing devices, rather than list prices the Assessment Group had used a weighted average of HRG codes because they included the costs of the whole procedure. The Committee noted that a weighted average could disguise the true cost of more expensive devices. However, it heard from the clinical experts that there was no incentive for clinicians to use unnecessarily expensive dualchamber devices. The Committee also noted the Assessment Group had conducted a threshold analysis on the impact of device costs on the ICER. This indicated that the price difference between dual and singlechamber atrial pacemakers had to be increased substantially, and to a level unlikely to be seen in clinical practice, before dualchamber pacemakers would not be cost effective at a maximum acceptable ICER of 20,000 per QALY gained.
Incorporation of healthrelated qualityoflife benefits and utility values
Have any potential significant and substantial healthrelated benefits been identified that were not included in the economic model, and how have they been considered?
The Committee noted that there were no statistically significant differences shown for quality of life. However dualchamber pacemakers had been clearly demonstrated to statistically significantly reduce the need for reoperation, which could be unpleasant and severe. The Committee concluded this was a significant benefit for patients.
Are there specific groups of people for whom the technology is particularly cost effective?
Not applicable.
n/a
What are the key drivers of cost effectiveness?
The Committee agreed that there were high levels of uncertainty in the Assessment Group basecase ICERs, as a list price for the devices was not available to use in the model. However the threshold analysis had demonstrated that the price difference between dual and singlechamber atrial pacemakers had to be increased substantially, and to a level unlikely to be seen in clinical practice, before dualchamber pacemakers would not be cost effective at a maximum acceptable ICER of 20,000 per QALY.
In sensitivity and scenario analyses, most ICERs were under 20,000 per QALY gained.
Most likely costeffectiveness estimate (given as an ICER)
The Committee agreed that the basecase ICER of approximately 6000 per QALY gained was likely to be higher in clinical practice because there is no difference in the effectiveness of dualchamber pacing for outcomes including heart failure. Dualchamber pacemakers also have higher acquisition costs; however this cost is likely to be partially offset by the reduced need for reoperation. The Committee was further reassured by the threshold analysis that the price difference between dual and singlechamber atrial pacemakers had to be increased substantially, and to a level unlikely to be seen in clinical practice, before dualchamber pacemakers would not be cost effective at a maximum acceptable ICER of 20,000 per QALY gained. The Committee concluded that the most plausible ICER was likely to be under 20,000 per QALY gained.
For reviews (except rapid reviews): How has the new costeffectiveness evidence that has emerged since the original appraisal (TA88) influenced the current recommendations?
Several new trials have been published since the publication of TA88. In particular, DANPACE was a large highquality trial, providing the best evidence base for this appraisal. This indicated that dualchamber pacemakers were associated with a statistically significant reduction in the need for reoperation compared with singlechamber atrial pacemakers.
Additional factors taken into account
Patient access schemes (PPRS)
Not applicable.
n/a
Endoflife considerations
Not applicable.
n/a
Equalities considerations and social value judgements
Not applicable.
n/a# Review of guidance
The guidance on this technology will be considered for review 3 years after publication of the guidance. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators. Andrew DillonChief ExecutiveNovember 2014# About this guidance
NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS.
This guidance was developed using the NICE multiple technology appraisal process.
It partially updates NICE technology appraisal guidance 88 (published in February 2005). It replaces the first bullet point exception of TA88 only. TA324 now recommends dual chamber pacemakers for people with symptomatic bradycardia due to sick sinus syndrome and no evidence of atrioventricular block.
It has been incorporated into the NICE pathway on heart rhythm conditions along with other related guidance and products.
We have produced information for the public explaining this guidance. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.
NICE produces guidance, standards and information on commissioning and providing highquality healthcare, social care, and public health services. We have agreements to provide certain NICE services to Wales, Scotland and Northern Ireland. Decisions on how NICE guidance and other products apply in those countries are made by ministers in the Welsh government, Scottish government, and Northern Ireland Executive. NICE guidance or other products may include references to organisations or people responsible for commissioning or providing care that may be relevant only to England.
Your responsibilityThis 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 have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties.
Copyright National Institute for Health and Care 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.
ISBN: 9781473108479