Objective To assess the cost-effectiveness of implantable loop recorders (ILRs) and tilt testing (TT) to direct pacing therapy in people with recurrent episodes of transient loss of consciousness that are adversely affecting their quality of life or represent a high risk of injury and are suspected to be vasovagal.
Design Decision analytical modelling was used to estimate the costs and benefits of diagnostic testing including the costs and benefits of treatment for several clinically important arrhythmias following diagnosis.
Setting A UK National Health Service and personal social services perspective was taken.
Patients People with recurrent episodes of transient loss of consciousness that are adversely affecting their quality of life or represent a high risk of injury and which are suspected to be vasovagal.
Interventions The diagnostic test strategies compared were TT alone, TT followed by ILR (if TT ‘negative’), ILR alone and no further testing.
Main outcome measures Benefits measured using quality-adjusted life years and incremental cost-effectiveness ratios (ICER) are reported.
Results The ICERs for TT alone, ILR alone and TT followed by ILR were £5960, £24 620 and £19 110, respectively, compared with no testing. ILR alone was extendedly dominated by the other strategies, meaning that it is never the most cost-effective option. Sensitivity analysis found that the cost-effectiveness estimates were robust despite the areas of uncertainty identified in the evidence and assumptions used to inform the model.
Conclusions TT alone is likely to be the most cost-effective strategy in this population.
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Implantable loop recorders (ILRs) can document arrhythmias during episodes of transient loss of consciousness (TLoC) and can therefore be useful for directing pacing therapy, but evidence is needed on their cost-effectiveness. TLoC is common, affecting up to half the UK population over their lifetime.1 A common cause is vasovagal syncope (VVS), which may be a ‘simple faint’ but can also cause more dramatic TLoC in some people. It may be mediated by a cardioinhibitory or vasodepressor mechanism or a mixture of both.2 For most people, treatment of VVS requires education regarding measures to avoid recurrence and reassurance regarding its benign nature.2 Cardiac pacing may be warranted in people having frequent episodes which significantly reduce their quality of life or which place them at risk of injury.2 However, cardiac pacing only treats the cardioinhibitory component of VVS; before recommending pacing, it is necessary to determine whether a cardioinhibitory response (bradycardia or asystole) is present during VVS. ILRs are able to provide symptom–ECG correlation during spontaneous syncope and can therefore be considered the reference standard for identifying cardioinhibitory behaviour during spontaneous syncope.2 A lower cost alternative to ILR monitoring is tilt testing (TT), although the mechanism of syncope induced during TT may differ from that observed during spontaneous syncope.3 The optimal timing of ILR monitoring within the diagnostic pathway should be determined in terms of both clinical and economic viability.4
The National Institute for Health and Clinical Excellence (NICE), which publishes guidance for the UK NHS, has developed a clinical guideline on the management of TLoC in adults and young people.1 Determining appropriate diagnostic tests for people with TLoC was a key aspect of the guideline's scope. The guideline panel wanted to assess whether TT or ILRs should be used as a means of directing pacing therapy in people with suspected VVS who experience frequent episodes of TLoC or episodes that place them at risk of injury. In the diagnostic algorithm of the guideline, patients are considered to have suspected VVS if, after obtaining a detailed history, conducting a physical examination and recording a 12-lead ECG, there are features suggestive of VVS and no features suggestive of an alternative diagnosis. TT is not recommended simply to confirm a clear clinical diagnosis of VVS. Full details of the diagnostic algorithm are available in the guideline.1 Given the benign nature of VVS and the fact that, at the time of guideline development there was only weak evidence regarding the benefits of pacing in this population, the NICE guideline panel was interested to compare diagnostic strategies using TT and ILR versus a strategy of no further diagnostic testing.1 NICE is required to consider the balance of costs and benefits when making recommendations.5 This decision analytical model was constructed to assess the cost-effectiveness of TT and ILRs to direct pacing therapy in patents with VVS as part of the development process to inform the 2010 NICE clinical guideline.
The cost-effectiveness model reported here evaluates three diagnostic strategies to direct pacing in people with suspected VVS who are experiencing frequent episodes of TLoC or episodes that place them at risk of injury. This population excludes those who have TLoC episodes that either are unexplained or have another suspected cause after initial assessment or specialist cardiovascular assessment; these populations are addressed in a separate cost-effectiveness analysis.6 The diagnostic strategies considered are: TT alone; ILR alone; and a combined strategy of TT followed by ILR when TT is ‘negative’ (does not provoke syncope accompanied by asystole). The comparator is no further testing. The model uses a decision tree structure to estimate the diagnostic outcomes from each strategy (figure 1). In order to capture the main consequences of diagnosis, the model also estimates the costs and benefits of treatment for several clinically important arrhythmias. In line with the methods used by NICE,5 we used a cost-utility approach in which benefits are measured using quality-adjusted life years (QALYs) and took a UK NHS and personal social services perspective. Costs and QALYs were discounted at 3.5%.
Costs of testing
The costs of diagnostic procedures (TT and ILR implantation and removal) were based on NHS reference costs.7 The ILR device cost was based on a published estimate from 2004,8 which was uplifted to 2008 prices.9 A lower cost, assuming no increase from 2004, was examined in a sensitivity analysis. Unit costs applied in the model are summarised in table 1.
Diagnostic inputs and assumptions
Diagnostic inputs were assessed by systematic review of the literature, full details of which are reported in the guideline.1 Documentation of an ECG during spontaneous syncope was considered the reference standard for identifying patients with cardioinhibitory behaviour during spontaneous syncope who may achieve some symptomatic benefit from pacing. Data on the mechanism of syncope documented by ILR were therefore used to estimate the true prevalence of asystole during syncope across the population of the model.
Three studies examining the diagnostic yield of ILR in people with suspected VVS were identified.1 Diagnostic event rates across the three studies were similar.1 The diagnostic rates applied in the model were based on the largest of these, the International Study on Syncope of Uncertain Aetiology (ISSUE) 2 study.3 The population of that study was considered to be directly relevant to this economic model, as included patients had experienced three or more syncopal episodes in 2 years with severe clinical presentation (either a high number of episodes affecting quality of life or a high risk for injury) requiring treatment.
For the no-testing strategy we assumed that the underlying mechanism of syncope is identical to that seen in the ILR monitoring strategy, but that no patient receives a diagnosis. The probability of obtaining symptom–ECG correlation opportunistically during a future episode was considered small.
One study (ISSUE 2) provided sufficient information to determine the accuracy of TT against a diagnostic reference standard of ambulatory ECG in a population with suspected VVS, based on a subset of patients (94/392) who had had both a TT and a spontaneous syncopal event recorded by ILR.3 We defined a ‘positive’ TT as asystole during syncope and a ‘negative’ TT as either a mixed or vasodepressor response or bradycardia without asystole during syncope or an absence of syncope. Using these definitions we calculated the sensitivity and specificity of TT in identifying patients with asystole during spontaneous syncope. The diagnostic event rates applied in the model are summarised in table 2, and figure 1 shows how these probabilities were applied within the decision tree.
We restricted our analysis of outcomes following diagnosis to several key arrhythmias which were selected based on the potential impact of treatment on costs and QALYs. We assumed that patients with asystole during syncope would receive a dual chamber pacemaker. Patients with sudden-onset atrioventricular (AV) block with sinus rate increase (ISSUE type 1C) were considered separately from other categories of asystole (ISSUE types 1A/B) to allow for potential differences in treatment benefits. Those with ventricular tachycardia (VT) during syncope were assumed to receive an implantable cardioverter defibrillator (ICD) to reflect the fact that ILR monitoring is capable of finding clinically important arrhythmias other than asystole. The data used to determine the proportion of events attributable to AV block, other asystole and VT are summarised in table 2.
For patients receiving a pacemaker following a false-positive TT, we assumed that they would incur the costs of treatment and follow-up, but their health outcomes would be equivalent to untreated patients. For all other patients we made the simplifying assumption that diagnostic testing would have no significant impact on their future costs and health outcomes. This effectively ignores any change in patient management and outcomes that would result from observing a normal rate and rhythm during TLoC, an arrhythmia other than asystole or VT, or an absence of TLoC episodes during the lifetime of the device. This simplifying assumption will have underestimated the benefits of testing in these patients and this was considered when interpreting the cost-effectiveness results.
Modelling patient outcomes following diagnosis
We relied on existing technology appraisals and targeted literature searches to identify evidence on the cost and benefits of treatment following diagnosis. A systematic review of all treatment outcomes was not considered feasible because treatment of arrhythmias was not within the scope of the guideline. There was a lack of direct evidence regarding the long-term benefits of pacing in patients with asystole during syncope, so indirect evidence was applied from patients receiving pacing for either AV block or sick sinus syndrome (SSS). The methods used to model outcomes following diagnosis in this model are identical to those used in a related published model.6 Full details are also available in the published guideline and therefore only a summary of the key assumptions is provided here.1
A health-related quality of life (HRQoL) improvement was applied following pacing therapy for asystole (0.165, SE=0.02) and following ICD therapy in patients diagnosed with VT (0.117, SE=0.05).1 A sensitivity analysis examined the impact of assuming a lower HRQoL gain following pacing and no HRQoL gain following ICD therapy.
Six-year survival data from the Devon Heart Block and Bradycardia Survey study showed no survival gain from pacing in SSS but some survival gain from pacing in AV block.10 ,11 We used these data to estimate the survival gain for pacing in patients with AV block during syncope over 10 years. We assumed no survival gain for all other patients receiving pacing. A constant mortality rate from a population with SSS was applied.12 In a sensitivity analysis we considered the impact of assuming no survival gain in AV block. We also considered the impact of restricting the costs and benefits of pacing to 6 rather than 10 years.
The TLoC recurrence rate for patients with asystole in the 2 years after pacing was taken from a randomised trial comparing pacing with no treatment in patients with SSS.13 We assumed no further recurrences after 2 years. Since publication of the NICE guideline, further information has become available from the ISSUE 3 study on the cumulative rate of recurrence in paced (25% in year 1 and 25% in year 2) and unpaced (37% in year 1 and 57% in year 2) patients identified as having asystole during syncope by ILR monitoring.14 To assess the implications of these additional data, the 2-year recurrence rates from the ISSUE 3 study were applied in a sensitivity analysis.
The cost of pacing and the cost of TLoC recurrence were based on NHS reference costs and estimates from the published appraisal and are summarised in table 1.7 ,12 Admission for pacemaker implantation was considered in a sensitivity analysis as not all centres perform this as a day-case procedure. Given the uncertainty regarding recurrence rates beyond 2 years and the costs of recurrence, we tested the sensitivity of the model to these parameters by considering a scenario in which unpaced patients with asystole during syncope experience one recurrence resulting in admission per annum for 10 years.
For VT causing syncope, cost and QALY estimates from an existing published appraisal,15 which compared ICD therapy with anti-arrhythmic drug therapy, were adjusted to estimate the costs and QALY impact of ICD therapy relative to no treatment.1
Univariate sensitivity analyses were conducted to explore how sensitive the model results are to the various assumptions used to inform the model structure and to any uncertainties in the data used to populate the model. A probabilistic sensitivity analysis was conducted to explore the precision of the cost-effectiveness estimates. This examines variation in the cost-effectiveness outputs which arises from uncertainty surrounding the precision of the model inputs. The distributions used for each parameter can be found in appendix I of the published guideline.1
The model estimates that a strategy of using TT followed by ILR in those with a ‘negative’ TT would result in more patients correctly receiving pacing than the other two strategies (see table 3). Both strategies that employ TT result in some patients receiving inappropriate pacing therapy while both of the strategies that employ ILR result in some patients receiving appropriate ICD therapy.
The correct identification of patients for pacing and ICD therapy is predicted by the model to result in QALY gains over the lifetime of the cohort. The strategy of using TT followed by ILR (when TT is ‘negative’) is predicted to result in the highest QALY gain compared with no testing, followed by ILR alone and then TT alone. This is because most of the QALY gains occur through the correct identification of patients for pacing.
All three diagnostic strategies are estimated to result in an overall increase in cost compared with no testing, as the cost of testing and providing treatment following diagnosis is only partially offset by reductions in syncope recurrence. Post-diagnostic costs are highest for the strategy employing TT followed by ILR as these are mainly driven by treatment costs. The average costs and QALYs from 10 000 samples of the probabilistic sensitivity analysis are shown in table 3.
The incremental analysis in table 3 and the cost-effectiveness acceptability curve in figure 2 show that TT alone is the most cost-effective strategy when one is willing to pay between £6000 and £25 000 per QALY. If one is willing to pay more than £25 000 per QALY, TT followed by ILR is the most cost-effective strategy. It shows that a strategy of using ILR alone will never be cost-effective if the other two testing strategies are available. This is because one would need to be willing to pay over £38 000 per QALY to justify the additional cost of recommending ILR instead of TT. However, if this were true, logically one must also be willing to pay £25 000 per QALY to move from the TT strategy to the strategy of using TT followed by ILR, which has more QALY gains than ILR alone. In this situation we say that ILR alone is extendedly dominated by the other two testing strategies.
The univariate sensitivity analysis found that the cost-effectiveness of the three testing strategies is robust despite the areas of uncertainty identified in the evidence and assumptions used to inform the model (results shown in online supplementary material). The incremental cost-effectiveness ratio (ICER) was sensitive to some of the assumptions used within the model. In particular, the ICER increased when we assumed no survival gain from pacing or lower HRQoL gain from either pacing or ICD therapy. It also increased when we restricted the cost and benefits of pacing to only 6 years, as the main effect of this was to reduce the duration of benefits achieved by pacing. The model was not particularly sensitive to alternative assumptions regarding the rate or cost of recurrences, so there was little change in the results when applying recurrence rates from the ISSUE 3 study. None of the sensitivity analyses exploring key areas of uncertainty increased the ICER for TT versus no testing to above £30 000 per QALY and none reduced the ICER for the other strategies relative to TT to below £20 000 per QALY.
Our model showed that TT is likely to be the most cost-effective testing strategy to direct pacing therapy in people with suspected VVS who are experiencing frequent episodes of TLoC or episodes that place them at risk of injury. One strength of this analysis is that it incorporates estimates of the costs and benefits of treatment following diagnosis into the assessment of cost-effectiveness. NICE does not apply a rigid cost-effectiveness threshold, but its methods guidance suggests that interventions with an ICER under £20 000 are unlikely to be rejected on the basis of cost-effectiveness and those with an ICER above £30 000 are likely to be rejected on the basis of cost-effectiveness.5 TT was considered to be the most cost-effective strategy because it had an ICER under £20 000 per QALY while alternative strategies involving ILR monitoring had less favourable ICERs.
Our analysis had several limitations which were explored through sensitivity analysis. There was a lack of direct evidence regarding HRQoL and long-term prognosis following pacing in patients with asystole detected by ILR during VVS, so indirect evidence was applied from patients with AV block and SSS. This may have overestimated the benefits of pacing because patients with asystole during VVS could be less responsive to pacing therapy as it does not affect vasodepressor mechanisms that may also contribute to episodes of syncope. This may have biased the cost-effectiveness analysis in favour of the ILR strategy which identifies more patients for pacing than the TT strategy. There was also considerable uncertainty regarding HRQoL gains following treatment for VT causing syncope due to a lack of direct evidence for this population. There was also uncertainty regarding potential long-term cost savings from preventing syncope recurrence. The conclusion that TT is the most cost-effective strategy was not altered when making alternative assumptions in these areas of the model during sensitivity analysis.
Another key limitation is that the model fails to account for the potential benefits to patients who have an arrhythmic cause excluded by diagnostic testing. These patients may not receive any active treatment for their TLoC, but their quality of life may be improved by knowing that they do not have a life-threatening cause. Given that no benefit is assumed for these patients or for patients diagnosed with arrhythmias other than asystole or VT, it is likely that the model underestimates the cost-effectiveness of all three diagnostic strategies.
The European Society of Cardiology (ESC) syncope guideline includes a recommendation for using ILR in people with suspected or certain reflex syncope before embarking on cardiac pacing.2 While the ESC guideline provides some discussion of health economic considerations, it does not explicitly consider the cost-effectiveness of each recommendation.2 At the time the NICE guideline was developed, no published cost-effectiveness analyses relevant to the decision problem addressed here were identified, and therefore information on the relative cost-effectiveness of ILR and TT would not have been available to the ESC Guideline Task Force.1 The strength of the approach adopted by NICE is that it requires the guideline developers to consider explicitly the costs and benefits of all the relevant strategies, allowing the most cost-effective strategy to be identified.
Our cost-effectiveness model was developed to inform NICE guidance on the use of TT and ILR monitoring to direct pacing therapy in people with suspected neutrally-mediated syncope who are having episodes of TLoC which are frequent or which place them at risk of injury. NICE has recommended TT in this population because it considers it to be a more cost-effective use of NHS resources than alternative strategies which include ILR monitoring.
This work was conducted in collaboration with the NICE Guideline Development Group and the National Clinical Guideline Centre. Members of the Guideline Development Group are Paul Cooper (chair), Robin Beal, Mary Braine, Ian Bullock, Sarah Davis, Julie Fear, Melesina Goodwin, Richard Grünewald, Paddy Jelen, Fiona Jewkes, John Pawelec, Sanjiv Petkar, David Pitcher, Alison Pottle, Greg Rogers, Garry Swann and Maggie Westby. Additional contributing members from the National Clinical Guideline Centre are Paul Miller, Emma Nawrocki and Nancy Turnbull. Systematic review support was provided by Jacoby Patterson.
Contributors SD was the health economist who developed the cost-effectiveness model. MW conducted the systematic reviews of diagnostic evidence and provided advice to support model development. SP and DP provided clinical expertise which supported model development. All authors contributed to the drafting of the manuscript. SD is responsible for the overall content as guarantor.
Funding This work was undertaken by the National Clinical Guideline Centre which received funding from the National Institute for Health and Clinical Excellence. The views expressed in this publication are those of the authors and not necessarily those of the Institute.
Competing interests Conflicts of interest for all Guideline Development Group members including DP and SP can be found in Appendix B of the Full Guideline which can be accessed at http://www.nice.org.uk/nicemedia/live/13111/50435/50435.pdf. SD and MW have no conflicts of interest.
Provenance and peer review Not commissioned; externally peer reviewed.