Q J Med 2009; 102:349–356 doi:10.1093/qjmed/hcp025 Advance Access publication 10 March 2009

Commentary Expenditure and value for money: the challenge of implantable cardioverter defibrillators G. BORIANI, M. BIFFI, C. MARTIGNANI, I. DIEMBERGER, C. VALZANIA, M. BERTINI and A. BRANZI From the Institute of Cardiology, University of Bologna, Bologna, Italy

Summary Many technology-driven interventions entail considerable financial cost, raising affordability issues. The implantable cardioverter defibrillator (ICD) is a case of an effective primary prevention intervention with high initial costs that is capable of delivering long-term population benefits. At first glance, such interventions may provoke diffidence, if not active resistance, due to the financial burdens which

inevitably accompany their widespread adoption. In this article, we review the available economic tools that can help address the ICD cost issue. We think awareness of such knowledge may facilitate dialogues between physicians, administrators and policymakers, and help foster rational decisionmaking.

Introduction Technological advances are rapidly opening up new opportunities in the field of preventive and curative medicine. However, many effective new interventions entail considerable financial cost, raising affordability issues. Given the limited financial resources available, economic concerns are inevitably becoming increasingly important to physicians and other health care professionals who are not necessarily accustomed to dealing with such matters. Primary prevention is a particularly challenging area, since many years may pass before the benefits of the intervention can be perceived within the targeted population.1,2 At first glance, costly primary prevention initiatives may provoke diffidence, if not active resistance, due to the financial burdens which inevitably accompany their widespread adoption.3 For instance, part of the controversy currently surrounding plans for widespread human papillomavirus vaccination of preadolescent girls with the

aim of reducing the long-term burden of cervical cancer regards the initial overall costs.4 This issue is common to most preventive interventions in the public health field, including various mass cancer screening programmes (breast, colorectal, prostate, etc.).5 The implantable cardioverter defibrillator (ICD) is a challenging case of an intervention with high initial costs and deferred benefits, whose effectiveness has already been clinically demonstrated.6–11 Solid evidence now supports the role of ICDs not only in the setting of secondary prevention of sudden cardiac death (i.e. in patients with a previous aborted cardiac arrest or a previous life-threatening ventricular tachycardia) but also in the setting of primary sudden cardiac death prevention (for patients who had not previously experienced lifethreatening events). In recent years, evidence-based international guidelines have extended indications

Address correspondence to Prof. Giuseppe Boriani, Institute of Cardiology, University of Bologna, Via Massarenti 9, 40138 Bologna, Italy. email: [email protected] ! The Author 2009. Published by Oxford University Press on behalf of the Association of Physicians. All rights reserved. For Permissions, please email: [email protected]

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for a prophylactic ICD to increasingly broad patient populations.9–11 At the same time, the financial challenges of widespread implementation of such indications remain an important open issue.2,3,12 In this article, we will review the available economic tools that can help address the ICD cost issue. In the light of the available estimates, we will argue in favour of an ongoing cultural change in the way many physicians, administrators and policymakers view and approach this sort of cost issue.

The ICD cost issue Despite the decline in overall mortality from cardiovascular diseases observed over the last decade, the proportion of deaths due to sudden cardiac death has been increasing.13 In the West, sudden cardiac death is responsible for more victims each year than AIDS, lung cancer, breast cancer or stroke14. Evidence from a series of large randomized trials now provides very strong evidence that the use of ICDs improves overall survival at 2–5 years in appropriately selected patients with left ventricular dysfunction.7,8,11 In economically developed countries, the use of ICDs for primary prevention of sudden cardiac death can be seen as an important public health consideration.2 In the US, more than 100 000 ICDs were implanted during 2006.15 The vast majority (79%) of these implants were for primary prevention of sudden cardiac death, reflecting guideline implementation within the context of a national coverage policy.15,16 In Europe, the situation is inevitably much more variable, characterized by marked differences in ICD implantation rates between different countries with different approaches to public health care expenditure. The rates vary considerably even within western Europe: according to national registries, in 2005 the numbers of implants per million inhabitants were 60–70 in Sweden, UK, Norway and Spain; 115–140 in Switzerland, Belgium, Austria, Denmark and the Netherlands; 181 in Italy; and as many as 226 in Germany.17 These differences suggest very variable attitudes towards ICD therapy implementation, especially in the context of primary prevention.2,10 The ICD is commonly perceived as a rather expensive treatment with high up-front costs due to the device itself and the subsequent maintenance of the implant with costs for device replacement and possible complications.2 Despite marked price reductions in the last decade, the cost issue continues to limit full acceptance and adoption of ICD therapy, especially as regards widespread use for primary prevention of sudden cardiac death.2,18

Clearly, the ICD cost issue does not only regard electrophysiologists. Since most candidates for an ICD for primary prevention of sudden cardiac death are heart failure patients, the issue is relevant to all organizations involved in the care of patients with heart failure or left ventricular dysfunction (including primary care services and the outpatient/inpatient wings of internal medicine and cardiology clinics, etc.). The role of ICD therapy has expanded hugely since the device was first conceived by Dr Michel Mirowski over 25 years ago for secondary sudden cardiac death prevention in selected patients with documented ventricular tachyarrhythmias.19 Demonstrated efficacy of ICDs in primary prevention was initially established in patients with previous myocardial infarction and left ventricular dysfunction (MADIT I, MUSTT, MADIT II trials),6–11 and was then extended to patients with left ventricular dysfunction and heart failure (NYHA class II and III) of either ischaemic or non-ischaemic aetiology (SCD-HeFT trial).6–11 These findings were progressively translated into the recommendations for ICD implantation provided by consensus guidelines. Considering the evidence from the individual trials alongside the results of various meta-analyses of efficacy,7,8,11 it seems clear that ICDs are effective in improving overall survival in the medium-term in appropriately selected patients with left ventricular dysfunction at high risk of sudden cardiac death. In terms of relative risk, these benefits are additional to optimized pharmacological treatment, and appear even greater in primary than in secondary prevention trials (Figure 1). In the primary prevention trials, the number needed to treat to save one life (a measure derived from the absolute risk reductions shown in Figure 1) ranged from 3 to 18. A metaanalysis incorporating data from 10 primary prevention trials involving over 9000 patients (with ffi3500 interventions and 3700 controls) indicated that ICD treatment led to a reduction in all-cause mortality (relative risk, 0.75; 95% CI: 0.63–0.91)7 that can be considered highly significant from a population perspective. Guideline recommendations9 for selection of ICD implant candidates are based on a fairly straightforward translation of the eligibility criteria used in the most recent primary prevention trials (i.e. the MADIT II and SCD-HeFT). This approach is expected to lead to an impressive rise in the potential number of implants. In response to concerns that an increased use of ICDs may cause a dramatic financial burden on health care systems, a debate is emerging both among public health care providers and the wider medical community on how to find a balance between the weight of evidence

Defibrillators: Expenditure and value for money

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70 %

Mortality control group

60 50 40

Relative risk reduction ICD vs Control Absolute risk reduction ICD vs Control

44.4 35.9 31.5 27

30 20 11.3

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13.7 8

10 0 Study (time horizon)

*

*

18

3.7

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70

*

%

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59

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CIDS (3 yrs)

55 56.4

50 40

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38.6

36.8

* 28.3

31

30

29

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19

20 10 0 Study (time horizon)

5.6

MADIT (2.3 yrs)

*

23

22.8

MUSTT (5 yrs)

MADIT II (1.7 yrs)

7

COMPANION (1 yr)

7.2

SCD-HeFT (5 yrs)

Figure 1. Results of controlled intervention studies of the efficacy of ICDs in the setting of secondary prevention (top) and primary prevention (bottom) of sudden cardiac death. The bars show the overall mortality risk recorded for the control groups (during given study periods), alongside the reductions in relative risk and absolute risk recorded in the corresponding ICDintervention groups.

and spending on ICD therapy.2 What is the best approach to the cost issues raised by increasing indications for ICD implantation? Should implantation decisions directly implement the criteria for patient selection used in the clinical trials (a ‘pure’ evidence-based approach)? Or do we need to develop further criteria in order to deliver ICD implantation only to those patients who are most likely to benefit (a pragmatic approach dictated by currently available economic resources)? Whereas there is broad scientific consensus regarding the efficacy of using ICDs in appropriately selected patients, a search to reach a similar consensus on the cost issue appears more problematic. Despite the mounting costs that health care systems have had to face in recent years, in many high-income countries the balancing of benefits against costs has yet to become a primary criterion for deciding whether a medical treatment should be covered by public services (the UK National Institute of Clinical Excellence is a prominent exception in this respect). In many European countries, both policymakers and health care providers have largely focused on cost projections, with a consequent tendency to limit or even reject costly new

treatments, despite their confirmed clinical efficacy. In other words, consideration of the effects of adopting a new treatment has mainly been based on strictly financial concerns rather than on in-depth economic analysis.20 It has been authoritatively argued that ‘affordability’ considerations must be kept separate from clinical guidelines based on scientific evidence of efficacy.21 The affordability of relatively expensive treatments of clearly demonstrated efficacy is a delicate issue.22 Whereas the clinical efficacy of the treatment may apply across a wide range of human populations, affordability considerations will inevitably vary between countries with very different healthcare systems and economies. Nevertheless, analytical tools do exist to help address specific questions of affordability within national, regional or even local contexts.

Available tools for economic analysis A range of economic approaches exist that go beyond assessment of financial burden. Genuinely economic approaches include cost-effectiveness,

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cost-utility and cost-benefit analysis for assessment of competing candidate treatments.20 These tools address questions such as ‘which treatment is most likely to provide maximum health benefits for a given level of financial resources?’ or ‘which treatment provides a given level of health benefits at the lowest cost?’ The different approaches generate different measures.20 Cost-effectiveness estimates are expressed in terms of ‘years of life saved’ (YLS), and cost-utility evaluations as ‘quality-adjusted life years’ (QALY) gained. On the other hand, cost-benefit analysis directly assigns a monetary value to therapeutic benefits. However, all the approaches weigh up the benefits and costs of given medical treatments to provide a formal economic basis for implementation decisions. The ‘cost’ of a therapy is a global concept, encompassing both direct and indirect costs. Direct costs regard initial implementation, subsequent maintenance and any adverse effects. Indirect costs are those paid by patients, families and the community. Cost-effectiveness analysis aims to assess the cost of any therapeutic intervention with respect to its predictable outcome benefits20 (with the ‘effectiveness’ being measured as the mean YLS as a result of the treatment). Comparisons of alternative therapeutic strategies (‘incremental cost-effectiveness’ analysis) can generate a costeffectiveness ratio, often expressed in dollars per year of life saved ($/YLS). In the literature,18,20,23 treatments are sometimes referred to as being ‘very attractive’ when the cost-effectiveness ratio ranges between 0 and 20 000 $/YLS; ‘attractive’ between 20 000 and 40 000 $/YLS; ‘borderline’ between 40 000 and 60 000 $/YLS; ‘unfavourable’ between 60 000 and 100 000 $/YLS and ‘absolutely unfavourable’ above 100 000 $/YLS. Some examples of cost-effectiveness ratios are shown in Table 1. Cost-effectiveness ratios can vary considerably depending on the type of treated population, and identification of high-risk patients (‘patient targeting’)18 seems to be the single most important issue in order to reach a favourable figure. Remarkably, long-term use of relatively ‘cheap’ medications which do not exert major long-term survival benefits can generate unfavourable costeffectiveness ratios (examples include lipid lowering treatments in patients at relatively low risk, as well as antihypertensives and antithrombotic treatment with clopidogrel in specific subgroups of patients.18,26 Conversely, when high initial treatment costs are offset by long-term survival benefits – as can be the case with ICDs – the cost-effectiveness ratio may turn out to be surprisingly favourable.

Available economic estimates for the use of ICDs Table 1 shows cost-effectiveness estimates of ICD treatment in the context of values reported for a selection of other treatments (including cardiac resynchronization therapy with biventricular defibrillators – a separate issue which is beyond the scope of this review). These estimates were generated by economic models (projections) that used a variety of data sources, ranging from observational studies to the more recent, large-scale randomized trials.2,18,27,28,30,31 A broad range of cost-effectiveness ratios have emerged for ICDs, ranging from unfavourable to economically attractive values (including values close to or lower than other accepted treatments, such as renal dialysis, which costs 50 000–60 000 $/YLS).2,18,23 In general, analyses based on the recent randomized trials have provided less attractive cost-effectiveness ratios than those generated in the early modelling studies.2,18,28 A further source of variability is the time horizon within which costeffectiveness is estimated. Recent evaluations of MADIT II and SCD-HeFT trials31,32 clearly indicate that the cost-effectiveness of ICD treatment in primary prevention of sudden cardiac death becomes more favourable in the long term. In particular, values under 100 000 $/YLS, which in certain socioeconomic contexts could be considered feasible (even if not ‘attractive’), may be achieved only beyond a 8–12 year benefit horizon.31,32 An analysis based on SCD-HeFT trial data31 estimated an ICD cost-effectiveness value of 38 389 $/YLS within a lifetime horizon, indicating that its use in primary prevention may be acceptable and justifiable from the standpoint of cost-effectiveness. A modelling study evaluating the cost-effectiveness of prophylactic ICD vs control according to all the available primary prevention trials supporting ICD use concluded that within a lifetime horizon ICD treatment was associated with a life extension ranging from 1.40 to 4.14 years, with incremental cost-effectiveness ratios ranging from 24 500 to 50 700 $/YLS.28 In this study, a sensitivity analysis indicated that the cost-effectiveness ratio was below 100 000 $/QALY as long as the ICD reduced mortality (in comparison with conventional treatment) for at least 7 years. The most comprehensive available analysis on cost effectiveness was commissioned by NICE specifically for the UK national context.33,34 This study included a decision-analysis model based on evidence critically extracted from eight randomized

Defibrillators: Expenditure and value for money Table 1

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Cost-effectiveness of various treatments

Treatment

Cost per year of life saved ($/YLS)

Pacemaker for complete AV block Valve replacement for aortic stenosis Neonatal intensive care Simvastatin in CAD with hypercholesterolaemia (age 59, chol. 309 mg/dl) CABG for left main stenosis Aspirin Enalapril post MI CABG for 3-vessel disease Beta-blockers in low-risk MI ICD for VT/VF with EPS Primary Stent in PTCA ICD for MADIT I profile Clopidogrel for secondary prevention in patients with CAD ineligible for aspirin ICD for SCD-HeFT profile ICD for MADIT II profile Anti-hypertensive tx (DAP 95–104) CRT-D in COMPANION ICD for MADIT II profile ICD for SCD-HeFT profile Hospital haemodialysis CRT in CARE HF CABG in 2-vessel disease Lovastatin in primary prevention, chol. > 300 mg/dl, no RF, m, age 55–64 ICD for MADIT II profile PTCA in 1-vessel disease Clopidogrel for secondary prevention in all patients with CAD Neurosurgery for malignant tumour Lovastatin in primary prevention, chol. > 300 mg/dl, no RF, f, aged 45–54

1400 2200 7400 1200 (M) 3200 (F) 9200 11 000 10 200 18 500 20 200 25 700 26 800 27 000 31 000 38 400 39 000 41 900 43 000 50 500 50 700 59 500 63 900 72 900 78 300 78 600 109 000 130 000 320 000 2 024 800

Data on cost-effectiveness were derived from the literature. Estimates on ICD are in Italics. As shown, different estimates have been reported for ICD implantation according to MADIT II or SCD-HeFT profiles. Estimates are reported in $ per year of life saved, or in some cases, as reported, in $ per quality-adjusted year of life gained. Data from: Tengs et al.23, Kupersmith et al.24, Johannesson et al.25, Boriani et al.18, Gaspoz et al.26, Al-Khatib et al.27, Sanders et al.28, Calvert et al.29, Feldman et al.30, Mark et al.31, Zwanziger et al.32.  : $ per quality-adjusted year of life gained; ACS: acute coronary syndrome; AV: atrio-ventricular; CABG: coronary artery by-pass graft; CAD: coronary artery disease; chol.: cholesterol; CRT: cardiac resynchronization therapy; DAP: diastolic arterial pressure; EPS: electrophysiological study; f: female gender; m: male gender; MI: myocardial infarction; PTCA: percutaneous transluminal coronary angioplasty; RF: risk factor; VF: ventricular fibrillation; VT: ventricular tachycardia.

controlled trials, two systematic reviews and a metaanalysis. Taking into account both secondary and primary prevention, the results indicated that ICD use can lead to variable survival improvements, with incremental cost-effectiveness values ranging from 98 000 to over 379 000 $/QALY depending on mortality risk and the assumptions adopted.34 This commissioned work exemplifies how costeffectiveness analysis can be applied to a specific national context to guide rational health care decision-making. As regards cost-benefit analysis, to our knowledge there is only one currently available study of ICDs in primary prevention of sudden cardiac death.

This study35 challenges the widespread assumption that ICDs should be viewed as a worrying financial burden for society. The researchers used the results of SCD-HeFT to compare cost-benefit values estimated for ICDs in comparison with amiodarone (the most widely used prophylactic antiarrhythmic drug). The conclusion was that in countries where society values a life at more than E2 million, ICDs can be considered a more worthwhile long-term investment than amiodarone for primary prevention of sudden cardiac death.35 This cost-benefit evaluation may radically change the perspective of ICD use in high-risk patients, supporting the view that this option can be seen as a worthwhile investment not

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only for individual patients, but also for society as a whole.36 It may also be helpful to reconsider the ICD cost issue in purely financial terms. The non-linear nature of the investment (characterized by high initial implantation expenditure, followed by a deferred pay-off in terms of clinical benefits) has led to the perception that ICD is a costly treatment option. We have suggested that estimation of the ‘cost-per-day’ of ICD treatment may help set the issue of the high up-front device costs in a more familiar perspective, closer to that of pharmacological treatments.20 We calculated that over a 7-year time horizon, the average daily costs associated with ICDs were estimated to be E4.20–4.80 for single and dual-chamber ICDs, respectively (E6.10–7.00, respectively, over a 5-year time horizon).37 Improved risk stratification may allow identification of patients for whom the option of ICD implant appears more favourable or attractive.38,39 Better patient targeting based on improved risk stratification might help optimize health outcomes within the context of financial restrictions. Assessment of the risk of sudden cardiac death set against the competing risk of non-sudden cardiac death could facilitate appropriate ICD cost-effectiveness estimates.40 Available ICD cost-effectiveness estimates currently tend to be limited by use of short/mid-term data as a basis for long-term projections. Another limitation regards the use of data from highly regulated clinical trials to estimate the benefits of ICDs deployed in broader real-world settings. Since clinical trials involving ICDs have generally been stopped as soon as improved survival has been statistically demonstrated, the follow-up has tended to be far shorter than the life expectancy of many patients implanted with an ICD in everyday practice.41 This factor is highly relevant since in the absence of sufficiently long follow-up data regarding ICD-related survival benefits, costeffectiveness estimates may be unduly penalized by the high initial cost of the device.2,18 Large registries could be used for generation of long-term cost-effectiveness projections based on realworld rather than experimental data. Such information could be especially valuable for health care systems.

Conclusions Despite continuing price reductions, the cost of ICDs will probably remain a major issue in implementation of current guidelines.42 Physicians responsible for decisions likely to affect patients’

future well-being may be confronted by ‘social’ limitations (limited economical funding) which compete with ‘individual’ imperatives (offering the best to each patient). The problem of how broadened evidence-based indications for implantation – in the form of internationally recognized clinical guidelines – can be translated into routine clinical practice will therefore need to be addressed in the light of locally available economic resources.21 In this article, we have tried to illustrate how economic analysis (in the form of costeffectiveness, cost-utility or cost-benefit estimates) can provide a key tool to weigh ICD costs against projected long-term outcome benefits. Since great emphasis has been traditionally placed on the relatively high up-front costs of ICDs, this approach seems appropriate in assessing whether implantation in specific subsets of patients will eventually be more or less economically valid in comparison with alternative treatments involving more continuous (‘chronic’ rather than ‘acute’) costs. Most studies indicate that the use of ICDs in appropriately selected patients at high risk of sudden cardiac death is associated with cost-effectiveness ratios similar to, or better than, other accepted treatments, such as renal dialysis. To set the high up-front costs of ICDs in a broader perspective, it may be useful to make long-term estimates of the ‘cost-per-day’ (thereby allowing comparisons with familiar pharmacological treatments). We think that there is a widespread cultural need to recognize that (in the words of NICE) ‘something can be both expensive and value for money’.43 This principle may apply to ICDs for primary prevention of sudden cardiac death in specific subsets of patients within given national or regional settings. Greater familiarity with this economic concept among physicians, administrators and policymakers may facilitate dialogue, and help foster rational decision-making for the allocation of available resources.

Acknowledgements Robin M.T. Cooke provided writing assistance (under contract with the University of Bologna).

Funding ‘Fondazione Luisa Fanti Melloni’, Universita` di Bologna, Bologna, Italy (partial). Conflict of interest: None declared.

Defibrillators: Expenditure and value for money

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40. Owens DK, Sanders GD, Heidenreich PA, McDonald KM, Hlatky MA. Effect of risk stratification on cost-effectiveness of the implantable cardioverter defibrillator. Am Heart J 2002; 144:440–8. 41. Ramsey S, Willke R, Briggs A, Brown R, Buxton M, Chawla A, et al. Good research practices for cost-effectiveness analysis alongside clinical trials: the ISPOR RCT-CEA Task Force report. Value Health 2005; 8:521–33. 42. Sutton R, Fisher JD, Linde C, Benditt DG. History of electrical therapy for the heart. Eur Heart J Suppl 2007; 9:I3–I10. 43. National Institute for Health and Clinical Excellence. A guide to NICE. London. April 2005: 1–18.