MADIT II/SCD-HeFT Results: Have They Already Achieved an Impact in Europe?

MADIT II/SCD-HeFT Results: Have They Already Achieved an Impact in Europe?

A. A

, M. O

Sudden cardiac death (SCD) is among the most common causes of death in developed countries, and even though there has been a reduction in total cardiac mortality, the percentage of deaths that are sudden has increased.

This has resulted primarily from an increase in out-of-hospital sudden deaths. Moreover, SCD is the first presentation of cardiac disease in 33–50%

of patients. Coronary artery disease is the most common underlying disease, being responsible for approximately 75% of all SCDs. The two most impor- tant risk factors for SCD are a left ventricular ejection fraction (LVEF) less than 40% and clinical congestive heart failure. The risk of mortality related to ejection fraction increases markedly when the LVEF falls below 40%.

Interestingly, the incidence of SCD decreases from NYHA functional class I to class IV. It is most frequent in class II patients: in this setting, more than half of patients will die suddenly. As result of these epidemiological charac- teristics, primary prevention of SCD has targeted patients with coronary artery disease and congestive heart failure and significant depression of LVEF, which means mainly patients in functional classes II and III [1–4].

The MADIT II study included patients with a LVEF of less than 30% with a prior infarct (more than 1 month before enrollment) and no other risk stratification criteria. The study enrolled 1232 patients, 60% of whom received ICDs versus 40% who received conventional therapy. MADIT II was stopped before its completion after a follow-up period of 20 months, when a 30% relative reduction in mortality was demonstrated. However, the absolute reduction was only 5.6%. Although the MADIT II inclusion criteria have been accepted as a class IIA indication for ICD implantation, there is signifi- cant controversy regarding costs and applicability to the general population [5]. Like most ICD studies, MADIT II mainly enrolled patients who were hos-

Cardiology Department, Hospital General Universitario Gregorio Marañón, Madrid,

Spain

pitalised, i.e. they were high-risk patients undergoing treatment. The mortal- ity rate of the control group in MADIT II is probably higher than the mortal- ity rate of patients who meet the enrollment criteria but who are found in a different setting.

The SCD-HeFT study randomised patients with clinical heart failure on stable medical therapy to (1) ICD plus optimal pharmacological therapy, (2) optimal pharmacological therapy plus amiodarone, or (3) optimal pharma- cological therapy. This study included patients with heart failure with or without ischaemic heart disease in NYHA classes II–III and LVEF of 35% or less. To avoid the deleterious effect of right ventricular pacing, back-up pac- ing was not triggered until the heart rate dropped to 34 bpm and was set to pace at only 50 bpm. The mean LVEF of the 2521 patients enrolled was 25%, 70% of patients were in NYHA class II and the remainder were in class III, 52% of patients had ischaemic heart disease, and the mean QRS duration was 112 ms. With a median follow-up of 45.5 months, the mortality rate in the placebo group was 36.1% at 5 years or 7.2% per year. ICD therapy reduced all-cause mortality by 23% at 5 years.

As a result of these trials and other primary prevention trials, as occurred after MADIT I and MUSTT, the rate of ICD implantation is expected to increase significantly in the United States. However, in Europe the impact of these studies is still questionable. Although the incidence of SCD and sur- vival rates are similar in the US and in Western Europe, the implantation rate in Europe is still markedly lower: whereas in 2001 the implantation rate was 208 per 1 million inhabitants in USA, in Europe it was 44 per million.

According to the Medtronic Implantation Register, 50% of implants in the US and 23% of implants in Germany were for primary prevention. Undoubtedly the publication of the MADIT II trial has modified the indication for ICD implantation, but, if we compare the percentage of implantations between US and Europe, the impact seems to be geographically variable.

The next data must be considered with some caution since owing to the lack of national and transnational databases only partial information is available. In Germany only 8% of ICDs were implanted on the basis of a MADIT II indication (Guidant Implantation Records). In 2003, primary pre- vention, including patients fulfilling the MADIT II criteria, represented 10%

of a total of 1500 ICD implantations reported to the National ICD Database in Spain. In our institution only 12% of implants performed during 2004 were due to MADIT II indications.

Detailed screening of postinfarction patients suggests that more than 1000 patients per year should meet the MADIT II criteria just in Spain [6].

According to these data only a minority of patients who fulfill the MADIT II criteria are receiving an ICD. Why this imbalance between suitable candi- dates and treated patients? There are several possible reasons:

248 A. Arenal, M. Ortiz

1. Current guidelines do not consider a single trial, such as MADIT II, enough evidence for a class I indication.

2. Although MADIT II scores over MADIT I and MUSTT by avoiding com- plex, time-consuming, and expensive screening processes for candidates, the results of the latter two trials were markedly superior. Both showed a 55% reduction in total mortality and a 75% reduction in SCD. In MUSTT, there was an absolute reduction of SCD of 23%. This meant that three devices had to be implanted to save one life. Cost-effectiveness analyses of these studies suggested a cost of $16 000 to $22 000 per year of life saved – an extremely cost-effective result. In MADIT II there was no sig- nificant effect on mortality during the first year of follow-up; moreover, the absolute risk reduction was 5.6%. Therefore, in this trial around 18 ICDs are needed to save a life. In agreement with these observations, we have reported that despite their having a lower LVEF, MADIT II patients have a lower incidence of ventricular tachycardia (VT) and sustained VT than do MUSTT/MADIT I patients. No differences were found between MUSTT patients and secondary prevention patients [7].

3. In the SCD-HeFT trial all-cause mortality at 5 years was reduced by only 23% in the ICD group compared with placebo. The trial suggests that only about one patient in 10 will benefit from an ICD over 3–5 years.

Moreover, the ICD benefit seems to be concentrated in patients from Canada and New Zealand, who had a 63% reduction in mortality, com- pared to an 18% reduction in mortality in US patients.

Conclusions

The MADIT II study and the SCD-HeFT studies suggest that the ICD reduces total mortality in patients with patients with LV dysfunction. However, the cost-effectiveness of this treatment makes it far from affordable. Better selec- tion of patients that could benefit from an ICD might increase the cost-effec- tiveness and decrease the percentage of patients in whom an ICD will only produce inappropriate discharges and other undesirable effects. Subgroup analysis has demonstrated a progressive increase in effectiveness of the ICD as QRS duration increases. Little benefit was derived in patients with a QRS of less than 0.12 s, whereas if a QRS duration of 0.15 s was used as a cut-off, a marked reduction in SCD was observed, comparable to that in MUSTT and MADIT I. Similarly, in the SCD-HeFT trial the relative benefits of ICD thera- py appeared greater in patients with NYHA class II heart failure, the group in which sudden death is expected to predominate. There seemed to be no benefit in patients with NYHA class III heart failure.

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MADIT II/SCD-HeFT Results: Have They Already Achieved an Impact in Europe?

References

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