4 Evidence and interpretation
4.1.1 Outcomes against which the relative effectiveness of dual‑chamber and single‑chamber 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.
4.1.2 The Assessment Group searches identified 32 studies of dual‑chamber pacemakers versus single‑chamber ventricular pacemakers. Four parallel randomised controlled trials (RCTs) allocated a total of 7006 patients to single‑ or dual‑pacing modes (MOST and PASE studies), or single‑ or dual‑chamber devices (CTOPP and the unpublished UKPACE study).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 single‑chamber ventricular pacing or 'physiological' pacing where the device used maintains the heart's natural AV synchrony (dual‑chamber pacing in atrioventricular block with or without sick sinus syndrome, and single‑chamber 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 dual‑chamber pacing or single‑chamber ventricular pacing.
4.1.3 There was no statistically significant difference in the incidence of mortality or stroke with dual‑chamber pacing compared with single‑chamber 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.
4.1.4 The incidence of atrial fibrillation associated with dual‑chamber pacing compared with single‑chamber ventricular pacing varied among the four large RCTs. The cumulative incidence of atrial fibrillation was up to 21.4% in the dual‑chamber pacing arm and 27.1% in the single‑chamber ventricular pacing arm. The proportional reduction in the relative risk of atrial fibrillation with dual‑chamber pacing reached significance in two of the studies (MOST: adjusted hazard ratio 0.77, 95% confidence interval [CI] 0.64 to 0.92; and CTOPP: reduced annual risk with dual‑chamber pacing of 18%, 95% CI 5.5 to 43.6%). A meta‑analysis 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 dual‑chamber pacing (odds ratio 0.76, 95% CI 0.65 to 0.90). A meta‑analysis incorporating the results of the unpublished UKPACE trial was also made available, in confidence, to the Appraisal Committee.
4.1.5 The MOST study had the highest power to detect differences in the incidence of atrial fibrillation with dual‑chamber pacing and single‑chamber 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 non‑chronic 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 non‑dependency) of 1% with dual‑chamber pacing (95% CI 0.2 to 1.8%; p = 0.01) and 0.7% with single‑chamber ventricular pacing (95% CI 0 to 1.4%; p = 0.04) for every 1% increase in the proportion of ventricular beats paced.
4.1.6 Two published RCTs (MOST and CTOPP) reported a lower incidence of heart failure with dual‑chamber pacing (which reached significance in one of the studies) compared with single‑chamber ventricular pacing. Results of the meta‑analysis of these two studies showed no overall difference in the rate of heart failure with dual‑chamber pacing compared with single‑chamber ventricular pacing (pooled odds ratio 0.83; 95% CI 0.66 to 1.05). A meta‑analysis incorporating the unpublished UKPACE trial was also made available, in confidence, to the Appraisal Committee.
4.1.7 A meta‑analysis of the 20 crossover studies showed a statistically significant improvement in exercise capacity with dual‑chamber pacemakers compared with single‑chamber ventricular pacemakers (standardised mean difference 0.35, 95% CI 0.17 to 0.52; p < 0.0001). These benefits were evident when dual‑chamber pacemakers were compared with non‑rate‑responsive single chamber ventricular pacemakers (standardised mean difference 0.49, 95% CI 0.1 to 0.89; p < 0.01). A meta‑analysis of exercise capacity with dual‑chamber pacing compared with single‑chamber 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 meta‑analysis of perceived exercise capacity reported in eight crossover studies showed a statistically significant improvement with dual‑chamber pacing (standardised mean improvement 0.68; 95% CI 0.29 to 1.08).
4.1.8 A meta‑analysis of 12 studies reporting global measures of QoL, obtained using visual analogue scales, showed a statistically significant improvement in QoL with dual‑chamber pacing compared with single‑chamber ventricular pacing. Three of the four RCTs evaluated QoL using the SF‑36 (UKPACE data on QoL was not available for the Assessment Report). The MOST study reported statistically significant improvements in QoL with dual‑chamber 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 short‑term at 9‑month but not at 18‑month follow‑up. The CTOPP study did not provide a separate analysis of dual‑chamber versus single‑chamber ventricular pacing.
4.1.9 The four large RCTs reported large variations in the incidence of pacemaker syndrome with single‑chamber 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 single‑chamber ventricular pacing to dual‑chamber pacing as a result of pacemaker syndrome. A meta‑analysis (based on the assumption that pacemaker syndrome does not occur in dual‑chamber pacing) of the three published RCTs showed a statistically significant reduction in the incidence of pacemaker syndrome with dual‑chamber pacing compared with single‑chamber 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 dual‑chamber pacing (standardised mean difference –0.88; 95% CI –1.13 to –0.62). A meta‑analysis incorporating the results of the UKPACE trial was also made available, in confidence, to the Appraisal Committee.
4.1.10 Literature searches identified one small parallel RCT and two crossover RCTs that randomised a total of 211 patients with sick sinus syndrome to dual‑chamber pacing or single‑chamber 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.
4.1.11 The parallel RCT reported a statistically significant lower incidence of atrial fibrillation with single‑chamber atrial pacing compared with dual‑chamber pacing (7.4% for single‑chamber atrial pacing; 20% for dual‑chamber pacing; p = 0.03), but no statistically significant difference in mortality (all‑cause or cardiovascular mortality), the incidence of heart failure or stroke, functional status (based on specific activity scale scores) or QoL.
4.1.12 One crossover study in 19 patients showed a statistically significant improvement in exercise tolerance based on bicycle ergometer tests with single‑chamber atrial pacing compared with dual‑chamber pacing (single‑chamber atrial pacing 103 watts, SD 31, compared with dual‑chamber pacing 96 watts, SD 27; p < 0.05).
4.1.13 The incidence of development of atrioventricular block in patients who received single‑chamber atrial pacing was variable, ranging from an annual incidence figure of 1.9% in the parallel RCT to a prevalence of 37% found during follow‑up in one of the crossover studies.
4.1.14 The crossover studies reported no difference in the presence of symptoms of cardiac dysfunction (palpitations, dizziness, chest pain) with dual‑chamber pacing compared with single‑chamber atrial pacing.
4.2.1 Literature searches identified one systematic review of the cost effectiveness of dual‑chamber pacing in patients with sick sinus syndrome, sick sinus syndrome with atrioventricular block or unspecified bradycardia, who were eligible for dual‑chamber or single‑chamber pacing. The studies included in this review were of limited relevance because they did not incorporate effectiveness data from the recent large parallel‑group RCTs, because results were not presented as cost per quality‑adjusted life year (QALY), and because of the technological developments in dual‑chamber pacing.
4.2.2 Three models were submitted to the Institute by consultees, and the Assessment Group also developed two separate Markov models that compared dual‑chamber with single‑chamber pacing according to whether the underlying cause of bradycardia was sick sinus syndrome or atrioventricular block.
4.2.3 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 5‑year time horizon. Dual‑chamber 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 dual‑chamber pacing: assumptions of 0% severe pacemaker syndrome with single‑chamber pacing increased the ICER of dual‑chamber pacing to £10,444 per QALY.
4.2.4 Guidant submitted a Markov model of the costs and outcomes of dual‑chamber pacing compared with single‑chamber ventricular pacing in a population of patients with sick sinus syndrome and atrioventricular block over a 10‑year time horizon. Dual‑chamber pacing was associated with an incremental cost of £742 and incremental benefits of 0.399 QALYs over 10 years compared with single‑chamber ventricular pacing, giving an ICER of about £1800 per QALY. Sensitivity analysis of the cost effectiveness of dual‑chamber pacing in younger patients (50 years of age, over a 30‑year time horizon) showed the dominance of dual‑chamber pacing, which was less costly and generated more QALYs than did single‑chamber pacing.
4.2.5 St Jude Medical submitted a model that compared the costs and outcomes of dual‑chamber with single‑chamber pacing in patients with atrioventricular block and sick sinus syndrome, or sick sinus syndrome alone, over a 7.5‑year time horizon. Dual‑chamber 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 dual‑chamber pacing.
4.2.6 The Assessment Group developed separate models that compared the cost and outcomes of dual‑chamber compared with single‑chamber pacing in populations of patients with sick sinus syndrome and atrioventricular block over a 10‑year time horizon. The atrioventricular block model compared dual‑chamber with single‑chamber ventricular pacing, and the sick sinus syndrome model compared dual‑chamber with single‑chamber atrial pacing. The models were similar in structure. A hypothetical cohort of 2000 75‑year‑old 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 1‑monthly 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 single‑chamber ventricular pacing arm); generator expiry; upgrade to a dual‑chamber 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.
4.2.7 Baseline estimates of the effectiveness of single‑chamber pacing were based on trials identified in the systematic review. The relative effectiveness of dual‑chamber pacing was incorporated into the model by applying the relative risk estimates from the meta‑analysis or from individual trials to the baseline parameters.
4.2.8 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 cost–utility analysis (see Section 3.2). The proportion of rate‑responsive single‑ and dual‑chamber pacemakers used in the model was based on the proportion of rate‑responsive and non‑rate‑responsive 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 dual‑chamber 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 single‑chamber devices.
4.2.9 Utility estimates were based on the PASE trial (in which a time trade‑off 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.
4.2.10 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 single‑chamber ventricular pacing arm. Patients with severe pacemaker syndrome were upgraded to a dual‑chamber pacemaker. Mild pacemaker syndrome was chronic. The progression of atrioventricular block in sick sinus syndrome was modelled only in the single‑chamber atrial pacing arm; these patients were upgraded to a dual‑chamber device. When atrial fibrillation occurred with dual‑chamber pacing, devices were reprogrammed to single‑chamber ventricular pacing and patients assumed the same risk of atrial fibrillation, stroke and heart failure as with single‑chamber ventricular pacing.
4.2.11 The base‑case 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). Dual‑chamber 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 dual‑chamber pacing decreases as benefits are accrued over a 10‑year time horizon, giving an ICER of £5500 per QALY.
4.2.12 One‑way 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 dual‑chamber pacing in atrioventricular block. However, the cost effectiveness of dual‑chamber pacing is sensitive to variations in price difference between dual‑ and single‑chamber pacemakers and assumptions about the incidence and resolution of mild pacemaker syndrome. A sensitivity analysis that evaluated the cost effectiveness of dual‑chamber pacing based on the market price of devices supplied by the ABHI (Section 3.3) resulted in ICERs of £7000 per QALY (over a 5‑year time horizon) and £4600 per QALY (over a 10‑year time horizon). Another sensitivity analysis varied the price of pacemakers to approximate the minimum (dual‑chamber £5200, single‑chamber atrial and ventricular pacemaker £4600), average (dual‑chamber £6500, single‑chamber atrial and ventricular pacemaker £4900) and maximum (dual‑chamber £8400 and single‑chamber atrial and ventricular pacemaker £5300) list prices of pacemakers. At the minimum and average assumed list prices of pacemakers, dual‑chamber 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.
4.2.13 The results of the model of dual‑chamber pacing in sick sinus syndrome demonstrated that dual‑chamber pacing is dominated by single‑chamber atrial pacing, because atrial pacing generates more QALYs and is less costly than dual‑chamber pacing. Sensitivity analysis showed that single‑chamber atrial pacing dominates dual‑chamber pacing in all scenarios.
4.3.1 The Committee reviewed the evidence available on the clinical and cost effectiveness of dual‑chamber pacing, having considered evidence on the nature of the condition and the value placed on the benefits of dual‑chamber 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 single‑chamber ventricular pacing separately from those with single‑chamber atrial pacing. It was also mindful of the need to take account of the effective use of NHS resources.
4.3.2 The Committee considered evidence on the benefits and risks of dual‑chamber pacing compared with single‑chamber 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, single‑chamber ventricular pacing for sick sinus syndrome without atrioventricular block). The Committee was also aware that RCT evidence from patients with a mean age of 73–80 years may not be applicable to younger patients. The Committee heard from experts that dual‑chamber pacemakers are associated with a higher incidence of perioperative complications and that the lifetime of a dual‑chamber pacemaker is likely to be 1 year less than a single‑chamber ventricular pacemaker. The Committee accepted expert testimony of the significant quality of life and clinical benefits associated with dual‑chamber 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 dual‑chamber pacemakers and potential need to replace dual‑chamber pacemakers up to 1 year earlier than single‑chamber ventricular pacemakers.
4.3.3 The Committee reviewed all the data and economic models on the cost effectiveness of dual‑chamber pacing compared with single‑chamber 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 single‑chamber ventricular pacing, and pacemaker syndrome‑like symptoms may also occur with dual‑chamber pacing, albeit infrequently. The Committee also considered that the disutility associated with mild pacemaker syndrome, and therefore the cost effectiveness of dual‑chamber 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 dual‑chamber pacing, the Committee concluded that dual‑chamber pacing is cost effective even when conservative assumptions around the effects of pacemaker syndrome are considered (see sensitivity analysis discussion, section 4.2.12).
4.3.4 The Committee considered the cost effectiveness of dual‑chamber pacing compared with single‑chamber 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 dual‑chamber pacing over single‑chamber 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, dual‑chamber pacing is still likely to be a cost‑effective alternative to single‑chamber ventricular pacing.
4.3.5 The Committee agreed with expert opinion that dual‑chamber 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. Single‑chamber ventricular pacing is the clinically appropriate pacing mode for these patients.
4.3.6 The Committee considered the evidence on the clinical effectiveness of dual‑chamber pacing compared with single‑chamber atrial pacing for sick sinus syndrome. The Committee also acknowledged expert testimony indicating that in this population, single‑chamber ventricular pacing is not clinically appropriate because of the risk of pacemaker syndrome. The available evidence indicated that single‑chamber atrial pacing is likely to be more clinically effective than dual‑chamber 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 single‑chamber atrial pacing over single‑chamber ventricular pacing in sick sinus syndrome.
4.3.7 Although the evidence indicated the benefits of single‑chamber atrial pacing, the Committee was aware that some people with sick sinus syndrome who receive a single‑chamber atrial pacemaker may subsequently develop atrioventricular block, and would then require an upgrade to a dual‑chamber 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 1–2% 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 single‑chamber atrial pacing is suitable for these patients.
4.3.8 The Committee appreciated that rate‑responsive dual‑ and single‑chamber pacemakers are more costly but may confer additional benefits compared with non‑rate‑modulating devices. However, based on the evidence presented and the cost‑effectiveness analysis, the Committee concluded that decisions about whether to implant a rate‑responsive or a non‑rate‑responsive device should be made using clinical judgement on an individual patient basis.
4.3.9 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, dual‑chamber pacing is preferred to single‑chamber pacing. The Committee, however, recognised that in certain specific circumstances, single‑chamber pacemakers were more clinically appropriate. Single‑chamber 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, single‑chamber ventricular pacing is contraindicated and dual‑chamber pacing is associated with an increased incidence of atrial fibrillation. Similarly, single‑chamber ventricular pacing is the clinically appropriate pacing mode for people with atrioventricular block with continuous atrial fibrillation (dual‑chamber pacing is contraindicated in this group).
4.3.10 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 single‑chamber ventricular pacing, which should then be made on an individual patient basis, taking into consideration the risks and benefits associated with each pacing mode.