European Journal of Heart Failure

European Journal of Heart Failure 2003 5(4):419-425; doi:10.1016/S1388-9842(03)00099-0

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© 2003 European Society of Cardiology

Cardioverter-defibrillators after MADIT-II: the balance between weight of evidence and treatment costs

Giuseppe Boriani^*, Mauro Biffi, Cristian Martignani, Claudia Camanini, Francesco Grigioni, Claudio Rapezzi and Angelo Branzi

Istituto di Cardiologia, Università degli Studi di Bologna, Azienda Ospedaliera S.Orsola-Malpighi, Bologna Via Massarenti 9, 40138 Bologna, Italy

^* Corresponding author. Tel.: +39-51-349858; fax: +39-51-344859

	Abstract

Top Abstract 1. Introduction 2. Evidence supporting ICD... 3. Cost-effectiveness 4. MADIT-II and clinical... 5. Existing evidence 6. Upcoming data 7. Conclusions References

 
The possibility of using implantable cardioverter-defibrillators (ICDs) for primary prevention of sudden death in selected high-risk patients has prompted a series of prospective controlled studies. Recently, the MADIT II study highlighted the possibility of effective primary prevention of sudden death in patients with coronary artery disease selected by straightforward clinical data and without expensive screening (electrophysiological study). For patients with previous myocardial infarction and low left ventricular ejection fraction (30%), ICD implantation may reduce mortality risk by approximately 31% in the following 2 years. Implementation of this therapeutic strategy threatens to impact on public health-care spending. Possible cost-limiting mechanisms include price cuts because of increasing usage (market forces); identification of subgroups at higher risk of sudden death and use of cheaper devices with limited diagnostic and therapeutic options. Further long-term evaluation of the cost-effectiveness and cost-utility of ICDs should identify subgroups of patients for whom implantation is affordable despite current economic constraints. For heart failure patients, randomized controlled trials are currently evaluating the effects on overall survival of both conventional ICDs and devices with biventricular pacing capabilities. In this perspective, data from the COMPANION trial are expected to stimulate the use of devices with defibrillation back-up in candidates for biventricular pacing.

Key Words: Cardioverter-defibrillator • Coronary artery disease • Sudden death • Ventricular tachyarrhythmias

Received October 2, 2002; Revised April 17, 2003; Accepted May 15, 2003

	1. Introduction

Top Abstract 1. Introduction 2. Evidence supporting ICD... 3. Cost-effectiveness 4. MADIT-II and clinical... 5. Existing evidence 6. Upcoming data 7. Conclusions References

 
The implantable cardioverter-defibrillator (ICD) is considered an expensive treatment option, with the large initial outlay possibly being followed by replacement costs. Reduced hospitalization following the advent of transvenous implantation has encouraged more widespread use of ICD systems. Nevertheless, major differences in implant rates persist between the United States and Europe, as well as among different European countries [1–3].

	2. Evidence supporting ICD prophylaxis

Top Abstract 1. Introduction 2. Evidence supporting ICD... 3. Cost-effectiveness 4. MADIT-II and clinical... 5. Existing evidence 6. Upcoming data 7. Conclusions References

 
A series of controlled trials has validated the use of ICDs in specific subsets of patients, both for primary and secondary prevention of sudden cardiac death. Table 1 summarizes the results of these trials, in terms of the ability to improve overall survival [4–11]. These findings prompted the definition of appropriate guidelines for ICD use [12,13]. It is difficult to assess the degree of compliance to these guidelines in daily practice. However, indirect evidence suggests that even in the US the actual rate of implantation is lower than projections based on current guidelines [14]. Strict application of the definitive AVID criteria for ICD implantation in the field of secondary prevention of sudden death would probably lead (in the UK at least) to an escalation of implants and related costs [15]. Despite recent price reductions, the problem of cost remains a major determinant for full acceptance and application of ICD therapy.

View this table: [in this window] [in a new window]   Table 1 Prospective controlled trials on treatment with ICD vs. control in primary and secondary prevention of sudden cardiac death

 
Indications for devices with cardioverter-defibrillation capabilities are also expected to increase in view of the increasing interest in cardiac resynchronization therapy in patients with severe heart failure [16]. Biventricular pacing can improve quality of life and exercise capacity and reduce hospitalizations due to heart failure [17]. A recent meta-analysis [18] also indicated that biventricular pacing reduces mortality due to progressive heart failure. Particularly strong impetus for wider use of ICDs should come from the recently interrupted COMPANION trial [11,19]. This large randomized controlled trial, designed to evaluate biventricular pacing either alone or in conjunction with ICD, demonstrated a significant reduction in all-cause mortality when patients were treated with cardiac resynchronization therapy coupled with ICD [11].

	3. Cost-effectiveness

Top Abstract 1. Introduction 2. Evidence supporting ICD... 3. Cost-effectiveness 4. MADIT-II and clinical... 5. Existing evidence 6. Upcoming data 7. Conclusions References

 
Several authors have stressed the importance of analyzing the relationship between treatment costs and long-term benefits, both in economic and clinical terms [20–24]. Cost-effectiveness analysis aims to evaluate the cost of any therapeutic intervention in relation to its possible benefits [20,23–28]. The cost of a therapy is the sum of direct (initial, maintenance and complication-related) costs and of the indirect costs paid by patients’ families or the community. The effectiveness of a treatment is defined by the mean number of years survived after an adverse event due to intervention. Incremental cost-effectiveness analysis is generally based on comparison between two therapeutic strategies, the cost-effectiveness ratio being expressed in US dollars per year of life saved ($/YLS). A treatment is normally considered highly cost-effective [20,23–28] for ratios of 0–20 000 $/YLS, cost-effective for 20 000–40 000 $/YLS, borderline for 40 000–60 000 $/YLS, expensive for 60 000–100 000 $/YLS, and very expensive above 100 000 $/YLS. Table 2 summarizes cost-effectiveness analyses of ICD treatment generated by randomized trials, projections and retrospective analysis.

View this table: [in this window] [in a new window]   Table 2 Cost-effectiveness of ICD

 
In terms of primary prevention of sudden death, cost-effectiveness has been evaluated prospectively in the context of the original MADIT study [8], which enrolled patients with coronary artery disease, low left ventricular ejection fraction (0.35), non-sustained ventricular tachycardia and inducibility of ventricular tachycardia resistant to procainamide at electrophysiological study. Although subsequent analysis [35] revealed an acceptable cost-effectiveness ratio (27 000 $/YLS), it is clear that in some countries within Europe the conclusions of MADIT met some reservations and were not fully implemented [37].

Overall, analysis of use of ICDs in selected patients has most often revealed cost-effectiveness ratios that are comparable with or lower than other accepted treatments, including renal dialysis, which costs approximately 50 000–60 000 $/YLS [2,25–27,38]. Higher ratios were reported only in the context of the AVID [4,34] and CIDS [5,36] studies. Analysis of AVID [34] was limited by the assessment of charges instead of costs and by the relatively short follow-up. In CIDS, calculation of the cost-effectiveness ratio in the sickest patients (those with at least two risk factors for sudden death) led to a much more affordable cost-effectiveness ratio [36]. All the available studies agree that use of ICDs is associated with a favorable cost-effectiveness profile (i.e. <50 000 $/YLS) in patients with lower left ventricular ejection fraction, who have the highest risk of sudden cardiac death.

As regards patients with higher left ventricular ejection fraction, it has to be considered that the randomized controlled trials were not specifically designed for evaluation of cost-effectiveness. Furthermore, the mean follow-up of these studies is far shorter than the life expectancy of many patients implanted with an ICD in daily practice. This point is important, since the high initial cost of the device may markedly influence cost-effectiveness analysis, especially if the follow-up is not long enough to assess the full benefit [39]. When Hlatky and Bigger [39] projected the results of all the trials to gauge the full gain in life expectancy, they obtained a cost-effectiveness ratio of 31 500 $/YLS, in line with what is currently considered fully acceptable.

	4. MADIT-II and clinical practice

Top Abstract 1. Introduction 2. Evidence supporting ICD... 3. Cost-effectiveness 4. MADIT-II and clinical... 5. Existing evidence 6. Upcoming data 7. Conclusions References

 
The results of MADIT II [10] were published in March 2002. This trial was designed to investigate primary prevention of sudden death in patients with previous myocardial infarction (at least 1 month after any previous infarct), selected exclusively on the basis of reduced (30%) left ventricular ejection fraction. In the enrolled population, ICD implant reduced the risk of death by 31% during a 20-month follow-up. The results of MADIT II [10] should provide a strong impetus for wider use of ICDs. Nevertheless, at least two closely related problems still have to be addressed: the amount of currently available evidence and expense. Current guidelines do not consider data from a single trial, such as MADIT-II, to be sufficient for a class I indication. Against the backdrop of limited economic resources, this factor may delay its implementation. MADIT-II scores over MADIT-I and MUSTT by avoiding complex, time-consuming and expensive screening processes for candidates. Nevertheless, important economic questions remain to be solved. As mentioned in the study [10], approximately 400 000 new patients per year present with coronary artery disease and advanced heart failure in the US alone; frequent provision of an ICD implant would significantly impact on costs to national health-care systems.

There are at least three different approaches to the problem of how to implement MADIT-II. Firstly, the authors expressed the hope that market forces will drive down the cost of ICDs [10]. Secondly, in his accompanying editorial commentary, Bigger [40] proposed more careful screening of candidates, with identification within the MADIT-II study population of those patients who stand to benefit most from the ICD. A subsequent subgroup analysis of the MADIT-II study [41] showed that patients with wide QRS complex at baseline (>120 ms) had a greater reduction in total mortality with respect to the overall population. Finally, other ways could be found of cutting the price of ICD devices [42]. A proposal has been made to introduce less sophisticated ‘shock-only devices with a total capability of 8–10 shocks’ [43], marketed at a lower price to cut the cost of increasing ICD use. The idea of providing a ‘Volkswagen instead of a Rolls-Royce’ [43] is a possible way of limiting the financial burden on the health-care systems. However, in our view this particular proposal could have a series of clinical drawbacks, such as device exhaustion in case of arrhythmic storms or loss of full protection after delivery of some shocks (owing to limited shock capabilities). A possible alternative would be to adopt current simple single-chamber devices, which are cheaper than the sophisticated dual-chamber ones and provide good long-term reliability.

The problem of device cost will be compounded by the possibility of delivering shock therapy and biventricular stimulation with a single device. This pacing modality has been shown to improve quality of life and exercise capacity in patients with severe heart failure (NYHA class III–IV) and wide QRS complex [17,44]. Although the positive effects of ICDs with biventricular pacing on survival evidenced in the COMPANION trial [11] probably require further confirmation, sophisticated devices able to deliver biventricular pacing with independent left and right ventricular outputs as well as the entire spectrum of therapies for ventricular tachyarrhythmias (antitachycardia pacing, shock) are already available. These devices are the most expensive in the market. Therefore, plans to implement MADIT II must take into account the possibility of biventricular pacing. This option might be offered to selected patients to improve heart failure and reduce hospitalizations. Paradoxically, however, in the MADIT-II study these two end-points were not positively affected by ICD treatment in comparison with controls. On the contrary, despite a reduction in total mortality, ICD use actually led to an increased number of hospitalizations for heart failure [10].

The availability of devices able to terminate ventricular tachyarrhythmias and with proven efficacy in appropriately selected subsets of patients raises questions regarding the feasibility of an ICD-based strategy for sudden cardiac death prevention within a scenario of restricted health-care resources [43,45]. However, as Exner et al. [45] point out, if the first question is ‘Can we afford it?’, proven evidence of benefit raises a second question: ‘Can we afford not to do it?’. After MADIT-II, we have to move within an extremely delicate balance between evidence of efficacy and treatment costs. The difficulties and uncertainties in the decision-making process converge on the clinical cardiologist or electrophysiologist, who is the object of a series of influences dictated either by a ‘societal approach’ (limited economical resources) or by an ‘individual approach’ (offering the best to each patient).

	5. Existing evidence

Top Abstract 1. Introduction 2. Evidence supporting ICD... 3. Cost-effectiveness 4. MADIT-II and clinical... 5. Existing evidence 6. Upcoming data 7. Conclusions References

 
In the prospective controlled trials on ICD efficacy (Table 1), enrolment was based on clinical presentation and (for primary prevention trials) on some degree of left ventricular dysfunction; heart failure was not a specific inclusion criterion. Thus, these trials included patients with/without varying degrees of heart failure. For patients with ischemic (as opposed to idiopathic dilated) cardiomyopathy, data from MADIT and MADIT-II regarding severe left ventricular dysfunction (with/without advanced NYHA class) strongly support the use of ICDs for primary prevention of sudden death. However, for patients with idiopathic dilated cardiomyopathy and heart failure, the results of the CAT study [46] (a randomized controlled trial of patients with dilated cardiomyopathy of recent onset with left ventricular dysfunction and NYHA class II–III) did not show any advantage of ICD therapy in terms of mortality, which was low both in ICD-treated patients and controls. Another study, AMIOVIRT [47], compared amiodarone with ICD in non-ischemic cardiomyopathy and found no difference in outcome.

Interesting data regarding patients with idiopathic dilated cardiomyopathy came from an observational study by Grimm et al. [48]. In this study, patients with dilated cardiomyopathy, left ventricular ejection fraction 30% and non-sustained ventricular tachycardia after ICD implantation had the same incidence of appropriate interventions as patients presenting with syncope or ventricular tachycardia/fibrillation. Although this uncontrolled study was not prospective and adopted surrogate end-points, it may help identify a subset of patients with non-ischemic cardiomyopathy who could benefit from ICDs in primary prevention of sudden death.

It should also be noted that for patients with dilated cardiomyopathy, left ventricular dysfunction with severe heart failure and wide QRS complex, data from the COMPANION trial strongly support the validity of including cardioverter-defibrillation capabilities in devices implanted for cardiac resynchronization therapy [11,19].

	6. Upcoming data

Top Abstract 1. Introduction 2. Evidence supporting ICD... 3. Cost-effectiveness 4. MADIT-II and clinical... 5. Existing evidence 6. Upcoming data 7. Conclusions References

 
More data on the role of ICD therapy in heart failure patients are due to come from the SCD-HEFT trial [49]. In this study, ICD treatment is being prospectively compared with amiodarone and controls in patients with NYHA class II-III and left ventricular ejection fraction 35%. In view of the high risk of sudden cardiac death in heart failure patients, prospective studies are required to assess the role of ICDs in specific subsets of patients, especially those who are, or may become, candidates for transplantation. Such studies, which should also include patients with non-ischemic dilated cardiomyopathy, are essential for the definition of the ICDs in patients presenting with heart failure of varying severity and etiology. The ongoing DEFINITE and PRO ICD trials will address some of these questions [50]. As already mentioned, the role of combination therapy with ICD devices capable also of biventricular pacing needs to be evaluated in terms of efficacy and cost-effectiveness. The interruption of the COMPANION trial after demonstration of the advantages (in terms of reduction of deaths and hospitalizations) of cardiac resynchronization therapy [11,19] will provide an important stimulus for implantation of devices incorporating defibrillation capabilities. Although the full trial report is still awaited, it has been announced that use of ICDs plus biventricular pacing was associated with a 43% reduction in overall mortality with respect to optimized pharmacological treatment (Table 1) [11]. Subgroup analysis showed significant improvements in survival in the context of both ischemic and non-ischemic etiology. This finding could be particularly relevant, as it seems to provide the first support for use of ICDs in non-ischemic patients treated with biventricular pacing.

As with all expensive treatments, in the present climate of economic constraints, the cost-effectiveness and cost-utility of conventional ICDs, of pacemakers for biventricular pacing and of devices with both shock and pacing capabilities will have to be assessed in specific subgroups of patients [22].

	7. Conclusions

Top Abstract 1. Introduction 2. Evidence supporting ICD... 3. Cost-effectiveness 4. MADIT-II and clinical... 5. Existing evidence 6. Upcoming data 7. Conclusions References

 
In summary, following randomized controlled trials validating the use of ICDs in specific subsets of patients, both for primary and secondary prevention of sudden cardiac death, the problem of how the broadened indications can be transferred into clinical practice has to be addressed, in the light of currently available economic resources. Despite recent price reductions, cost represents a major determinant of full acceptance and application of ICD therapy. Randomized controlled trials indicate that in patients with lower left ventricular ejection fractions (who run the highest risk of sudden cardiac death), use of ICDs is associated with cost-effectiveness ratios similar to, or better than, other accepted treatments, such as renal dialysis. As regards patients with higher left ventricular ejection fractions, it has to be remembered that these trials were not specifically designed to assess cost-effectiveness and that their mean follow-up was far shorter than the life expectancy of many implanted patients, leading to possible underestimations of the full benefit.

The indications deriving from the MADIT-II trial on patients with ischemic heart disease threaten to impact strongly on health-care expenditure. Nevertheless, potential cost-limiting mechanisms do exist. These include price reductions because of increasing ICD use (dynamic market forces), identification of subsets of patients at higher risk of sudden death and use of cheaper ICD devices with circumscribed diagnostic and therapeutic options. Wider use of ICDs in sudden death prevention must also embrace heart failure patients; controlled studies are currently evaluating the effects on overall survival both of conventional ICDs and of devices incorporating biventricular pacing capabilities. Recent data from the COMPANION trial suggest that a reduction in all-cause mortality may be obtained by cardiac resynchronization therapy if the device has cardioverter-defibrillation capabilities.

In this complex scenario, a series of concerns in the decision-making process may arise, owing to the competing influences dictated by ‘societal approaches’ (limited economic resources) or by ‘individual approaches’ (offering the best to each individual patient). Specific evidenced-based indications and suggestions are urgently required on how to translate the results of controlled trials into daily clinical practice with individual patients within a context of limited economic resources.

	Acknowledgements

 
We are grateful to Robin M.T. Cooke for scientific editing.

	References

Top Abstract 1. Introduction 2. Evidence supporting ICD... 3. Cost-effectiveness 4. MADIT-II and clinical... 5. Existing evidence 6. Upcoming data 7. Conclusions References

 

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				G. Boriani, M. Biffi, A. Marziali, I. Diemberger, and C. Martignani A changing scenario in the clinical use of implantable defibrillators: the need for long-term data on lead performance Europace, January 1, 2009; 11(1): 1 - 3. [Full Text] [PDF]

				G. Boriani, R. Ricci, T. Toselli, R. Ferrari, A. Branzi, and M. Santini Implantable cardioverter defibrillators: from evidence of trials to clinical practice Eur. Heart J. Suppl., December 1, 2007; 9(suppl_I): I66 - I73. [Abstract] [Full Text] [PDF]

				G. Boriani, M. Biffi, C. Martignani, I. Mangat, F. Bokhari, D. Newman, M. Greene, V. Korley, and P. Dorian Letter Regarding Article by Bokhari et al, "Long-Term Comparison of the Implantable Cardioverter Defibrillator Versus Amiodarone: Eleven-Year Follow-Up of a Subset of Patients in the Canadian Implantable Defibrillator Study (CIDS)" * Response Circulation, January 25, 2005; 111(3): e26 - e26. [Full Text] [PDF]

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