A post hoc analysis of the Multicenter Automatic Defibrillator Implantation Trial (MADIT) II showed that patients with high mortality risk score did not benefit from implantable cardioverter-defibrillator (ICD) therapy. We sought to determine whether MADIT II risk score can identify patients with greater mortality in a nontrial “real-world” setting. We included 382 consecutive patients who received ICD for primary prevention of sudden cardiac death at the Minneapolis Veterans Affairs Medical Center from 2006 to 2010. MADIT II score was calculated by assigning 1 point each for age >70 years, New York Heart Association class >II, atrial fibrillation, QRS >0.12 seconds, and blood urea nitrogen level >26 mg/dl. Scores 0, 1 to 2, and ≥3 were classified as low, intermediate, and high risk, respectively. Of the 382 patients, 14% were low risk, 54% intermediate risk, and 32% high risk. After 3.0 ± 1.6 years of follow-up, incidence of appropriate ICD shocks was similar (p = 0.21) across MADIT II risk score categories. However, mortality rate was 21, 54, and 134 per 1,000 patient-year follow-up in low, intermediate, and high-risk patients, respectively, p <0.0001. Compared with low-risk patients, mortality was 6.4× greater in high-risk patients (hazard ratio 6.36, 95% confidence interval 1.9 to 20.5; p = 0.002). The c-index for the MADIT II score for predicting death was 0.69 (95% confidence interval 0.63 to 0.75). In conclusion, MADIT II risk score successfully identified patients with greater mortality in a nontrial-based, primary-prevention ICD cohort.
In a post hoc analysis of the Multicenter Automatic Defibrillator Implantation Trial II (MADIT II), a risk stratification scheme that consisted of age, New York Heart Association functional class, atrial fibrillation, QRS duration, and blood urea nitrogen level was used to categorize patients into low, intermediate, and high-risk groups for mortality. After 8 years of follow-up, patients with low and intermediate risk, but not those in high-risk category, derived a significant survival benefit from implantable cardioverter-defibrillator (ICD) therapy. However, to our knowledge, The MADIT II risk score has not been tested in a nontrial “real-world” ICD population. Thus, we compared all-cause mortality and the incidence of appropriate ICD shocks in patients categorized into low, intermediate, and high risk groups per the MADIT II risk score.
Methods
This study was approved by the research and development committee of Minneapolis Veterans Administration Medical Center and the requirement for individual consent was waived.
We included 382 consecutive patients who underwent new ICD implantation or generator replacement for primary prevention of sudden cardiac death at the Minneapolis Veterans Administration Medical Center from 2006 to 2010. Patients with cardiac resynchronization therapy (n = 174) and those in whom ICD was implanted for secondary prevention of sudden cardiac death (n = 72) were excluded from this analysis.
The MADIT II score was calculated by assigning 1 point each for age >70 years, New York Heart Association functional class >II, atrial fibrillation, QRS duration >0.12 seconds, and blood urea nitrogen >26 mg/dl. Study patients were then categorized into low (risk score 0), intermediate (risk score 1 or 2), and high (risk score ≥3) risk subgroups ( Table 1 ).
| Variable | Low, n = 52 (%) | Intermediate, n = 208 (%) | High, n = 122 (%) |
|---|---|---|---|
| Age >70 yrs | 0 | 29 | 76 |
| New York Heart Association class III/IV | 0 | 23 | 49 |
| Atrial fibrillation | 0 | 41 | 73 |
| QRS >120 s | 0 | 46 | 87 |
| Blood urea nitrogen >26 mg/dl | 0 | 13 | 66 |
All patients with ICD underwent device interrogation every 3 months according to a standard protocol. The follow-up information was obtained from local device clinic records and the Veterans Administration National Device Surveillance Program. In this analysis, follow-up started with the procedure (either new device implantation or generator replacement) performed at our medical center. Appropriate ICD shocks were adjudicated by a cardiac electrophysiologist after reviewing intracardiac electrograms. Mortality was assessed using the Veterans Administration vital status records and social security death index.
Data are presented as mean ± 1 SD, percentages, or incidence rates. Comparisons of baseline characteristics of patients in low, intermediate, and high-risk score categories were made using 1-way analysis of variance for continuous variables and chi-square test for categorical variables. Cox regression analysis was used to examine the risk of death among MADIT II score categories. Kaplan-Meier survival curves were generated using time to death as the outcome variable and compared with log-rank test. Area under the receiver operating characteristics curve (c-index) was calculated to assess how well the MADIT II score could separate patients who died from those who survived. All comparisons were 2 sided. A p value <0.05 was considered statistically significant. Analyses were performed using SPSS statistical software version 19 (IBM Corporation, Armonk, New York).
Results
Baseline characteristics of the 382 study patients are listed in Table 2 . Patients were 68 ± 10 years old, 99% were men, and 74% had ischemic cardiomyopathy. A total of 52 patients (14%) were categorized as low risk, 208 (54%) as intermediate risk, and 122 (32%) as high risk per the MADIT II score. The patients in higher risk subsets were more likely to have cardiovascular co-morbidities ( Table 2 ).
| Variable | Low (n = 52) | Intermediate (n = 208) | High (n = 122) | p |
|---|---|---|---|---|
| Age (yrs) | 59 ± 6 | 65 ± 10 | 75 ± 8 | <0.0001 |
| Men | 99% | 99% | 99% | 1.00 |
| Ischemic cardiomyopathy | 73% | 74% | 73% | 0.83 |
| Ejection fraction | 31 ± 12 | 31 ± 11 | 32 ± 12 | 0.22 |
| Diabetes | 48% | 49% | 48% | 0.88 |
| Chronic kidney disease | 45% | 50% | 41% | 0.02 |
| QRS width (ms) | 101 ± 10 | 123 ± 31 | 154 ± 36 | <0.0001 |
| Heart rate (beats/min) | 71 ± 13 | 72 ± 14 | 70 ± 12 | 0.13 |
| β Blocker | 98% | 98% | 97% | 0.79 |
| Blood urea nitrogen (mg/dl) | 17 ± 4 | 20 ± 8 | 31 ± 14 | <0.0001 |
| Angiotensin-converting enzyme inhibitor or angiotensin receptor blocker | 84% | 81% | 86% | 0.05 |
| Diuretic | 61% | 69% | 55% | 0.002 |
During 3.0 ± 1.6 years of follow-up, 64 patients (17%) received ≥1 appropriate ICD shock and 85 patients (22%) died. The incidence of appropriate ICD shock in patients with low, intermediate, and high MADIT II risk scores were 99, 69, and 109 per 1,000 patient-year follow-up, respectively (p = 0.21). Compared with patients with low MADIT II risk score, the risk of appropriate shock was not statistically different in patients with intermediate (hazard ratio [HR] 0.69, 95% confidence interval [CI] 0.33 to 1.45; p = 0.33) or high-risk score (HR 1.1, 95% CI 0.51 to 2.38; p = 0.88).
Mortality rate increased with MADIT II risk category (21 vs 54 vs 134 per 1,000 patient-year follow-up in low, intermediate, and high-risk categories, respectively; p <0.0001). Compared with low-risk patients, the risk of death was 2.5× greater in intermediate-risk patients (HR 2.54, 95% CI 0.78 to 8.25; p = 0.12) and 6.4× greater in high-risk patients (HR 6.36, 95% CI 1.9 to 20.5; p = 0.002; Figure 1 ). The area under the receiver operating characteristics curve (c-index) for the MADIT II score for predicting death was 0.69 (95% CI 0.63 to 0.75).
