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Clinical and Economic Implications of the Multicenter Automatic Defibrillator Implantation Trial-II FREE

Sana M. Al-Khatib, MD, MHS; Kevin J. Anstrom, PhD; Eric L. Eisenstein, DBA; Eric D. Peterson, MD, MPH; James G. Jollis, MD; Daniel B. Mark, MD, MPH; Yun Li, MS; Christopher M. O'Connor, MD; Linda K. Shaw, MS; and Robert M. Califf, MD
[+] Article and Author Information

From the Duke Clinical Research Institute, Durham, North Carolina.


The results of this study were presented at the American College of Cardiology 52nd Annual Scientific Session, Chicago, Illinois, 30 March–2 April 2003.

Acknowledgments: The authors thank Kerry Lee, PhD, for critical review of the manuscript and Maqui Ortiz for editorial assistance and manuscript preparation.

Grant Support: In part by Guidant Corporation.

Potential Financial Conflicts of Interest: Consultancies: S.M. Al-Khatib (Guidant Corp.), D.B. Mark (Medtronic Inc.), C.M. O'Connor (Guidant Corp., Medtronic Inc.), R.M. Califf (Guidant Corp., Medtronic Inc.); Honoraria: S.M. Al-Khatib (Medtronic Inc., Guidant Corp.), D.B. Mark (Medtronic Inc.), C.M. O'Connor (Guidant Corp., Medtronic Inc.), R.M. Califf (Guidant Corp., Medtronic Inc.); Stock ownership or options (other than mutual funds): R.M. Califf (Guidant Corp., Medtronic Inc.); Grants received: S.M. Al-Khatib (Guidant Corp., Medtronic Inc.), D.B. Mark (Medtronic Inc.), R.M. Califf (Guidant Corp., Medtronic Inc.); Grants pending: D.B. Mark (Medtronic Inc.), R.M. Califf (Guidant Corp., Medtronic Inc.); Royalties: R.M. Califf (Guidant Corp., Medtronic Inc.).

Requests for Single Reprints: Sana M. Al-Khatib, MD, Duke Clinical Research Institute, 2400 Pratt Street, Durham, NC 27715.

Current Author Addresses: Drs. Al-Khatib, Anstrom, Peterson, Jollis, Mark, O'Connor, and Califf; Mr. Li; Mr. Eisenstein; and Ms. Shaw: Duke Clinical Research Institute, 2400 Pratt Street, Durham, NC 27715.

Author Contributions: Conception and design: S.M. Al-Khatib, K.J. Anstrom, E.L. Eisenstein, J.G. Jollis, C.M. O'Connor, R.M. Califf.

Analysis and interpretation of the data: S.M. Al-Khatib, K.J. Anstrom, E.L. Eisenstein, E.D. Peterson, J.G. Jollis, D.B. Mark, Y. Li, C.M. O'Connor, L.K. Shaw.

Drafting of the article: S.M. Al-Khatib, K.J. Anstrom, E.L. Eisenstein, D.B. Mark.

Critical revision of the article for important intellectual content: K.J. Anstrom, E.L. Eisenstein, E.D. Peterson, J.G. Jollis, D.B. Mark, Y. Li, C.M. O'Connor, L.K. Shaw, R.M. Califf.

Final approval of the article: S.M. Al-Khatib, K.J. Anstrom, E.D. Peterson, J.G. Jollis, D.B. Mark, Y. Li, C.M. O'Connor, L.K. Shaw, R.M. Califf.

Provision of study materials or patients: E.D. Peterson.

Statistical expertise: K.J. Anstrom, E.D. Peterson, Y. Li, L.K. Shaw.

Obtaining of funding: S.M. Al-Khatib, R.M. Califf.

Administrative, technical, or logistic support: R.M. Califf.

Collection and assembly of data: S.M. Al-Khatib, K.J. Anstrom, Y. Li, L.K. Shaw.


Ann Intern Med. 2005;142(8):593-600. doi:10.7326/0003-4819-142-8-200504190-00007
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Editors' Notes
Context

The Multicenter Automatic Defibrillator Implantation Trial (MADIT)-II has shown that implantable cardioverter defibrillators (ICDs), compared with conventional therapy, appreciably improve survival in patients who have had a myocardial infarction and have an ejection fraction of 0.3 or less. However, the cost of following these recommendations has not been adequately assessed.

Contribution

Implantable cardioverter defibrillators are projected to improve survival by 1.80 discounted years, with an incremental cost-effectiveness ratio of $50 500 per life-year gained. Sensitivity analysis shows that the cost of replacing ICD batteries and leads exerts greater effect on cost-effectiveness ratios than other factors.

Implications

The large number of patients eligible for ICDs under MADIT-II criteria may strain societal ability to perform and pay for these procedures.

–The Editors

Sudden cardiac death is a major public health problem in the United States and claims the lives of approximately 300 000 people annually (1). Therapy with implantable cardioverter defibrillators (ICDs) has been proven to reduce the risk for sudden cardiac death in certain patient populations, including survivors of cardiac arrest caused by ventricular tachycardia or fibrillation and patients with a history of myocardial infarction (MI), an ejection fraction of 0.4 or less, nonsustained ventricular tachycardia, and inducible sustained ventricular tachycardia on electrophysiologic testing (24). In the Multicenter Automatic Defibrillator Implantation Trial (MADIT)-I and Multicenter UnSustained Tachycardia Trial (MUSTT), such patients had appreciably better survival with an ICD compared with antiarrhythmic medications or no antiarrhythmic therapy (34). The Multicenter Automatic Defibrillator Implantation Trial-II demonstrated that patients with a history of MI and an ejection fraction of 0.3 or less have a 31% relative risk reduction in mortality when treated with an ICD compared with conventional medical therapy (5).

While these studies have demonstrated the efficacy of ICD therapy, implantation and maintenance of ICDs are costly. To date, the cost-effectiveness of implanting ICDs in patients meeting MADIT-II criteria (that is, those with a history of MI and ejection fraction ≤0.3) is unknown. We assessed the long-term clinical and economic implications of implanting ICDs in all patients who meet the eligibility criteria for MADIT-II.

Study Sample

Our study sample consisted of patients at least 21 years of age who had a history of MI and an ejection fraction of 0.3 or less and underwent cardiac catheterization at Duke University Medical Center between 1 January 1986 and 31 December 2001. Patients who had had an MI within 30 days of catheterization were included only if they had more than 1 month of follow-up data available. Patients who underwent a revascularization procedure within 3 months of catheterization were included only if they had more than 3 months of follow-up data available. The study start date for these patients corresponds to either 1 month after MI or 3 months after the revascularization procedure, respectively. The start date for all other patients is the date of catheterization.

Patients were excluded from this analysis if they had New York Heart Association class IV symptoms, advanced cerebrovascular disease, any condition other than cardiac disease associated with a high likelihood of death within 1 year, or no ejection fraction data. Patients who had a previously implanted ICD or who received an ICD after catheterization were also excluded. Criteria for implantation of ICDs at our institution over the years have been in accordance with guidelines on implantation of antiarrhythmia devices from the American College of Cardiology, the American Heart Association, and the Heart Rhythm Society. As a result of our exclusion criteria, none of the patients in our study received an ICD for a MADIT-II indication. We obtained the approval of our institutional review board before the inception of the study.

Data Collection

Data for the study were collected by using the Duke Cardiovascular Database. This database systematically compiles the clinical experience of all cardiology patients who had cardiac catheterization at Duke University Medical Center (67). Patient information available through the system includes symptoms at time of cardiac procedures, diagnoses, electrocardiographic findings, medications, severity of coronary artery disease, and measures of left ventricular function. The database incorporates post-hospital follow-up at 6 months, 1 year, and annually thereafter; follow-up is complete in 95% of patients (810). The National Death Index is periodically searched to monitor the survival of patients lost to follow-up.

Statistical Analysis
Baseline Characteristics

Baseline characteristics for the Duke cohort are presented as means (±SD) for continuous variables and as percentages for categorical variables. Statistical tests comparing the baseline characteristics of the Duke cohort with MADIT-II patients were based on the sufficient statistics (mean, frequency, and standard deviation) from the MADIT-II published data and the Duke cohort. Chi-square tests were applied for discrete variables, and 2-sample t-tests were used for continuous variables. Statistical significance was determined at the 2-sided 0.05 level.

Survival Comparisons

We compared survival distributions within 3 years to assess whether the short-term survival for the Duke cohort was similar to that of the MADIT-II population. To produce the MADIT-II survival curves, we scanned and plotted the published survival curves using digitization software (UnGraph 4.0, Biosoft, Ferguson, Missouri). Estimates of the area under the survival curves and the 3-year survival rate were used to quantify differences in survival between the MADIT-II and Duke populations.

We constructed a Cox regression model with adjustments for the severity of coronary artery disease, age, sex, and indicator variables based on a patient's study start date (11). To mirror ischemic heart disease and heart failure management in the MADIT-II era, the survival model was averaged over all patients, with the study start date adjusted to the most recent era (between 1998 and 2001).

Lifetime Survival Models

Patients in the Duke cohort had a maximum of 15 years of follow-up. To extrapolate from these data for a lifetime cost-effectiveness analysis, we constructed treatment-specific survival curves. The right-hand tail of the survival curves was created by estimating a log-hazard ratio comparable to the survival of an age- and sex-matched cohort from the U.S. population (1213). In this analysis, we assumed that this hazard ratio remained constant after 15 years.

The lifetime survival model for the hypothetical Duke ICD group was constructed by assuming a constant hazard ratio of 0.69, as observed in the ICD arm of MADIT-II. To test the importance of this assumption, we performed a sensitivity analysis that assumed that the benefit of an ICD remained at a hazard ratio of 0.69 for the 3 years following the study start date and increased to a hazard ratio of 1.00 thereafter.

Clinical Events

The Duke Information System for Clinical Computing (DISCC) database was used to obtain data on the following clinical events: MI, percutaneous coronary inter-vention, coronary artery bypass graft surgery, rehospitalization, and death. To adjust for censored data due to staggered entry, we calculated estimates for mean number of clinical events using a nonparametric partitioned estimator (14). We selected 5 evenly spaced time partitions: 0 to 3 years, 3 to 6 years, 6 to 9 years, 9 to 12 years, and 12 to 15 years. Within each time partition, we calculated the average number of events per year.

Medical Costs

Total in-hospital costs were estimated by using a series of regression models derived from the Global Use of Strategies To Open Occluded Coronary Arteries (GUSTO)-IIb Economic and Quality of Life Substudy (1415). The perspective of the analyses was societal, although some societal costs (nonmedical costs, outpatient care, and productivity costs) were omitted. All costs were converted to 2002 U.S. dollars.

Lifetime Medical Costs

To extrapolate medical costs beyond 15 years, we multiplied the average in-hospital medical cost per year alive by the remaining life expectancy. To calculate the lifetime cost for the Duke medical therapy group, we modeled the observed clinical events data for the initial 15 years and then extrapolated the clinical events for an entire lifetime. The clinical events data were then converted to costs by using a series of regression models from previously conducted clinical trials (1516).

Lifetime ICD Costs

Lifetime costs for the Duke ICD arm were separated into 2 categories: 1) in-hospital costs not directly related to ICD therapy and 2) costs directly related to ICD therapy. Medical costs not related to ICD therapy were estimated by multiplying the average cost per year alive for the medical therapy arm (as described earlier) by the projected survival for the ICD arm. This assumption reflects our understanding that ICDs reduce the risk for sudden cardiac death but not the other risks associated with having coronary artery disease and low ejection fraction.

To determine ICD-related costs, we developed a template for ICD placement, follow-up visits, and battery replacement based on practice standards at Duke University Medical Center. In our primary or base-case analysis, follow-up visits were scheduled at 3-month intervals and batteries were replaced every 5 years following the implantation. Rates of complications were based on a publication by Kennergren (17) and the Medtronic product performance report for the first quarter in 2003 (18). Professional fees for ICD placement were estimated by using North Carolina Medicare reimbursement rates. Hospital costs for ICD placement and common ICD complications (lead fractures, lead dislodgement, pocket hematoma, infection, cardiac perforation, and pneumothorax) were estimated by using cost data from Duke University Medical Center for patients with diagnosis-related groups (DRGs) of 514 or 515 (placement) and 110, 111, 144, or 145 (complications).

Cost-Effectiveness Analysis

We calculated the incremental cost-effectiveness ratio for ICD therapy versus medical therapy by dividing the incremental discounted costs by the incremental discounted survival. Discounting is the process of converting future dollars and future health outcomes to their present value. The survival benefit was estimated by calculating the area between the survival curves. Conventionally, therapies with a cost-effectiveness ratio of $50 000 per life-year gained or lower are considered economically attractive and those costing $150 000 per life-year gained or greater are considered economically unattractive (19). Costs and survival benefits were discounted at a rate of 3% per year according to the recommendations of the Panel on Cost-Effectiveness in Health and Medicine (2021).

Sensitivity Analyses

Our base-case analysis assessed the cost-effectiveness of ICD therapy given current expectations of costs and outcomes. Sensitivity analyses were conducted by varying the therapeutic effectiveness and cost of ICDs, rates of complications, frequency of follow-up visits and battery replacements, and the time horizon. In a 1-way sensitivity analysis (that is, an analysis in which one factor was varied at a time), ICD-related costs (professional and technical) were estimated by using North Carolina Medicare reimbursement rates rather than the Duke University Medical Center cost data. An additional sensitivity analysis was conducted by using quality-adjusted survival as the measure of effectiveness. In this analysis, the utility values assumed for both treatments that 1 year of life in the MADIT-II health state is equivalent to 0.88 year in optimal health (2223).

Role of the Funding Source

This study was funded in part by Guidant Corporation. All of the analyses were done independently by Duke investigators. Representatives of Guidant had no input into the design of the study, the acquisition and analysis of data, or the wording of the manuscript.

Baseline Characteristics

From 1986 through 2001, 51 001 patients underwent at least 1 cardiac catheterization at our institution. Of these, 1285 (2.5%) met our study's inclusion criteria. The primary reasons for exclusion were no history of MI (n = 39 255); ejection fraction greater than 0.3 (n = 15 292); or cardiac catheterization for primary valvular disease, congenital heart disease, restrictive or obstructive cardiomyopathy, or pericardial disease (n = 16 970). In Table 1 the baseline characteristics of the Duke cohort are compared with the baseline characteristics of the MADIT-II patients (medical therapy and ICD groups). Compared with patients enrolled in MADIT-II, patients in the Duke cohort were younger, underwent revascularization less frequently, had a higher mean ejection fraction, and had a shorter time between MI and enrollment.

Table Jump PlaceholderTable 1.  Comparison of Baseline Clinical Characteristics of the Duke Medical Therapy Group and Patients in the Multicenter Automatic Defibrillator Implantation Trial-II
Clinical Outcomes
Short-Term Survival

Overall, survival of patients in the medical therapy group was similar in the Duke and MADIT-II populations (3-year survival probability of 71% and 69%, respectively) (Figure 1). For the initial 3 years following study enrollment, the Duke cohort averaged slightly less survival time (2.46 years vs. 2.52 years). The Duke ICD group's 3-year survival probability and cumulative survival time were similar to those in the MADIT-II ICD group (79% and 2.62 years vs. 78% and 2.65 years, respectively).

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Figure 1.
Survival comparison of patients in the Multicenter Automatic Defibrillator Implantation Trial (MADIT)-II with patients in the Duke medical therapy and implantable cardioverter defibrillator (ICD) groups.

The estimated survival curves for the Duke medical therapy and ICD groups were adjusted to reflect a more recent era of ischemic heart disease and heart failure management (1998–2001).

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Extrapolated Survival

At 15 years, the adjusted survival estimate was 33.8% for the Duke ICD group versus 20.8% for the Duke medical therapy group. Beyond the 15th year, the ICD group was estimated to have an average of 1.00 additional year of survival compared with the medical therapy group (1.81 years vs. 0.81 year). As shown in Figure 2 the projected life expectancy for the ICD therapy group was 10.88 years compared with 8.26 years for the medical therapy group. Under our base-case assumption, ICDs were projected to result in an increase of 2.62 years undiscounted years in life expectancy versus conventional medical therapy.

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Figure 2.
Survival projections for implantable cardioverter defibrillator (ICD) therapy versus medical therapy.
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Clinical Events

In the Duke medical therapy group, most hospitalizations and coronary artery bypass graft surgery occurred in the initial 3 years. Coronary artery bypass graft surgery was 2.6 times more likely to occur in years 0 to 3 than in years 3 to 15 combined (Table 2). Approximately half of percutaneous coronary interventions occurred in the first 3 years.

Table Jump PlaceholderTable 2.  Clinical Events, Survival, and Medical Costs for the Duke Medical Therapy Group
Economic Outcomes

The base-case costs of ICD placement, follow-up, and maintenance are provided in Table 3. During fiscal year 2003, we observed that 77% of ICDs were implanted after cardiac catheterization (DRG 514) and 23% were implanted without cardiac catheterization (DRG 515). According to the practice standards of Duke University Medical Center, the average costs for DRG 514 and 515 were $42 416 and $32 914, respectively. Average costs for ICD follow-up visits ranged from $70 to $89, depending on ICD type and reprogramming. The average cost for ICD battery replacement was $17 493.

Table Jump PlaceholderTable 3.  Costs for Placement of Implantable Cardioverter Defibrillators, Follow-up, Maintenance, and Complications

Over 15 years, the average undiscounted and discounted in-hospital costs were $42 552 and $37 661, respectively, for the Duke medical therapy group (Table 2). Total projected survival and medical costs for both Duke cohorts are presented in Table 4. In the medical therapy group, the estimated lifetime undiscounted medical costs were $47 721. For the ICD group, the combined undiscounted estimation of ICD-related and in-hospital (non-ICD) costs was $152 893 ($84 680 and $68 213, respectively).

Table Jump PlaceholderTable 4.  Projected Survival and Medical Costs for the Duke Medical Therapy Group and the Duke Implantable Cardioverter Defibrillator Group
Cost-Effectiveness

Tables 5 and 6 show the results of the cost-effectiveness analyses. In the base-case analysis, we estimated that ICD therapy would result in 1.80 discounted life-years gained at a cost of $90 829 (discounted). The incremental cost-effectiveness ratio is $50 500 per life-year gained. In the sensitivity analyses, cost-effectiveness varied dramatically with changes in time horizon: The cost-effectiveness ratio increased to $67 800 per life-year gained, $79 900 per life-year gained, $100 000 per life-year gained, $167 900 per life-year gained, and $367 200 per life-year gained for 15-year, 12-year, 9-year, 6-year, and 3-year time horizons, respectively.

Table Jump PlaceholderTable 5.  Results of Base-Case Analysis
Table Jump PlaceholderTable 6.  Results of One-Way Sensitivity Analysis

The average cost for ICD and leads placement was $19 370 in the base-case analysis. If these costs were reduced to $10 000, the incremental cost-effectiveness ratio would be $45 200 per life-year gained. Changing the frequency of follow-up visits, complication rates, and battery replacements had less of an effect on the cost-effectiveness ratios than reducing the cost of ICD placement and leads. When Medicare rates were used, the incremental cost-effectiveness ratio decreased slightly to $49 400 per life-year gained. If the efficacy of the ICD ended after 3 years, the estimated survival benefit would be 0.64 discounted life-year gained at an additional cost of $79 536, and the incremental cost-effectiveness ratio would be $123 400 per life-year gained (Table 6).

We examined the sensitivity of our analyses to variations in the mortality hazard ratio. In Figure 3 the relationship between cost-effectiveness and the mortality hazard ratio for ICD versus conventional medical therapy is illustrated. For our base case, hazard ratios below 0.69 and 0.84 resulted, with cost-effectiveness ratios below 50 000 per life-year gained and $100 000 per life-year gained, respectively. If ICD placement costs were reduced to $10 000, hazard ratios below 0.72 and 0.86 resulted in incremental cost-effectiveness ratios below $50 000 per life-year gained and $100 000 per life-year gained, respectively.

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Figure 3.
Cost-effectiveness of implantable cardioverter defibrillator (ICD) therapy versus medical therapy.

ICER = incremental cost-effectiveness ratio.

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Applying a utility of 0.88 to patients receiving ICDs and those receiving medical therapy resulted in a discounted quality-of-life–adjusted survival benefit of 1.58 years and an incremental cost-effectiveness ratio of $57 300 per quality-adjusted life-year gained.

This study showed that, among an unselected population of patients receiving cardiac catheterization, the number of patients meeting MADIT-II eligibility criteria is not small. In 2000, about 1 318 000 inpatient cardiac catheterizations were performed in the United States (24). If the Duke cardiac catheterization experience were generalized, our results imply that approximately 32 000 (2.5% of 1 318 000) of these patients meet MADIT-II criteria. The overall number of ICDs implanted in 2000 was 34 000 (24). Thus, implanting ICDs in all MADIT-II–eligible patients would at least double the annual number of ICD implants in the United States (32 000 plus 34 000).

On the basis of the MADIT-II findings, ICDs are projected to result in an estimated 1.81 discounted life-years gained if the effect of ICDs remains constant over time. Not surprisingly, the incremental cost-effectiveness ratio associated with that survival benefit is reasonably favorable ($50 500 per life-year gained). This ratio becomes more favorable ($45 200 per life-year gained) if the cost of the ICD system is reduced to $10 000. Although the cost-effectiveness ratio did not significantly change with a 1-year increase or decrease in battery longevity, the ratio becomes significantly more favorable ($42 200 per life-year gained) if the longevity doubles to 10 years. However, if the efficacy of the ICD ends after 3 years of follow-up, the incremental cost-effectiveness ratio ($123 400 per life-year gained) would be unfavorable. Under the 3-year survival benefit scenario, if the mortality hazard ratio is less than 0.61, the incremental cost-effectiveness ratio would be less than $100 000 per life-year gained.

Our study showed that patients seen in clinical practice who meet MADIT-II entry criteria are clinically different from patients enrolled in MADIT-II. Patients in the Duke cohort were younger, had a shorter time between MI and enrollment, had a higher mean ejection fraction, and underwent revascularization less frequently. The survival of the Duke cohort was slightly worse than that of patients randomly assigned to conventional therapy in MADIT-II. If sicker patients are more likely to derive survival benefit from an ICD, the resulting cost-effectiveness ratio would be more favorable than the one obtained for the base case in our study.

Comparing our results with those from other ICD cost-effectiveness analyses requires careful consideration of design features, including the time horizon (25). Among analyses using lifetime time horizons, our estimated cost-effectiveness was higher than that obtained by Larsen and colleagues (26)($41 000 per life-year gained) and Kuppermann and associates (27)($28 600 per life-year gained) but somewhat lower than results from Owens and coworkers (28)($63, 300 per life-year gained).

The base-case cost-effectiveness analyses from MADIT-I, the Antiarrhythmics Versus Implantable Defibrillator (AVID) trial, and the Canadian Implantable Defibrillator Study (CIDS) considered time horizons ranging from 3 to 6 years (2931). Our cost-effectiveness results are less favorable than results obtained from MADIT-I and the AVID trial. However, the results of our analysis with a 6-year time horizon ($166 000 per life-year gained) are similar to results obtained from CIDS ($138 800 per life-year gained in 1999 U.S. dollars). The main difference among these analyses is the time horizon. Although there is no standard time horizon for such analyses, the Panel on Cost-Effectiveness in Health and Medicine recommends that a lifetime horizon be used (2021).

Whether the health care system can afford to implant ICDs in all MADIT-II–eligible patients is not determined only by the monetary costs. Having enough personnel to implant and maintain these devices is equally important. While data on the number of ICDs implanted by each electrophysiologist in the United States are unavailable, it is safe to assume that the current number of electrophysiologists who can implant ICDs is far below the number required to meet the anticipated demand. National cardiology associations need to orchestrate their efforts in developing a plan to address the increasing need for personnel able to implant and follow ICDs.

Study Limitations

The degree of completeness of our data may limit our conclusions. The entire ICD group was extrapolated. Indeed, the most direct evidence relating to the cost-effectiveness of ICD therapy in patients who meet MADIT-II criteria will be provided by the cost-effectiveness analysis of the actual data gathered in MADIT-II. In addition, this analysis was based on patients referred for a cardiac catheterization. Because this involves referral bias, the findings of this analysis may not apply to other patients who meet MADIT-II criteria and are seen in other settings. The difference in the onset of enrollment between the Duke cohort and the MADIT-II cohort probably resulted in a significant difference in medical therapy between the 2 groups. Adjusting for this difference, however, did not alter our findings. Finally, we did not address potential upgrades to biventricular devices. However, because of the uncertain effect of biventricular pacing on survival and on heart failure hospitalizations, doing so would have required a new model with many assumptions and permutations.

Study Implications

Among an unselected cardiac catheterization population, the annual number of patients meeting MADIT-II criteria in the United States appears to be at least as large as the entire population who received ICDs for any indication in 2000. Thus, the resource implications of ICD implantation in all patients who meet MADIT-II criteria are substantial. Our study provides necessary assessment of the potential impact of implanting ICDs in all MADIT-II–eligible patients. In the range of survival benefit observed in MADIT-II, ICD therapy in these patients is economically attractive by conventional standards. This therapy would be even more attractive if its cost is reduced and its longevity is extended.

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Spath MA, O'Brien BJ.  Cost effectiveness of implantable cardioverter defibrillator therapy versus drug therapy for patients at high risk of sudden cardiac death. Pharmacoeconomics. 2002; 20:727-38. PubMed
 
Larsen GC, Manolis AS, Sonnenberg FA, Beshansky JR, Estes NA, Pauker SG.  Cost-effectiveness of the implantable cardioverter-defibrillator: effect of improved battery life and comparison with amiodarone therapy. J Am Coll Cardiol. 1992; 19:1323-34. PubMed
 
Kuppermann M, Luce BR, McGovern B, Podrid PJ, Bigger JT Jr, Ruskin JN.  An analysis of the cost effectiveness of the implantable defibrillator. Circulation. 1990; 81:91-100. PubMed
 
Owens DK, Sanders GD, Harris RA, McDonald KM, Heidenreich PA, Dembitzer AD. et al.  Cost-effectiveness of implantable cardioverter defibrillators relative to amiodarone for prevention of sudden cardiac death. Ann Intern Med. 1997; 126:1-12. PubMed
 
Mushlin AI, Hall WJ, Zwanziger J, Gajary E, Andrews M, Marron R. et al.  The cost-effectiveness of automatic implantable cardiac defibrillators: results from MADIT. Multicenter Automatic Defibrillator Implantation Trial. Circulation. 1998; 97:2129-35. PubMed
 
Larsen G, Hallstrom A, McAnulty J, Pinski S, Olarte A, Sullivan S. et al.  Cost-effectiveness of the implantable cardioverter-defibrillator versus antiarrhythmic drugs in survivors of serious ventricular tachyarrhythmias: results of the Antiarrhythmics Versus Implantable Defibrillators (AVID) economic analysis substudy. Circulation. 2002; 105:2049-57. PubMed
 
O'Brien BJ, Connolly SJ, Goeree R, Blackhouse G, Willan A, Yee R. et al.  Cost-effectiveness of the implantable cardioverter-defibrillator: results from the Canadian Implantable Defibrillator Study (CIDS). Circulation. 2001; 103:1416-21. PubMed
 

Figures

Grahic Jump Location
Figure 1.
Survival comparison of patients in the Multicenter Automatic Defibrillator Implantation Trial (MADIT)-II with patients in the Duke medical therapy and implantable cardioverter defibrillator (ICD) groups.

The estimated survival curves for the Duke medical therapy and ICD groups were adjusted to reflect a more recent era of ischemic heart disease and heart failure management (1998–2001).

Grahic Jump Location
Grahic Jump Location
Figure 2.
Survival projections for implantable cardioverter defibrillator (ICD) therapy versus medical therapy.
Grahic Jump Location
Grahic Jump Location
Figure 3.
Cost-effectiveness of implantable cardioverter defibrillator (ICD) therapy versus medical therapy.

ICER = incremental cost-effectiveness ratio.

Grahic Jump Location

Tables

Table Jump PlaceholderTable 1.  Comparison of Baseline Clinical Characteristics of the Duke Medical Therapy Group and Patients in the Multicenter Automatic Defibrillator Implantation Trial-II
Table Jump PlaceholderTable 2.  Clinical Events, Survival, and Medical Costs for the Duke Medical Therapy Group
Table Jump PlaceholderTable 3.  Costs for Placement of Implantable Cardioverter Defibrillators, Follow-up, Maintenance, and Complications
Table Jump PlaceholderTable 4.  Projected Survival and Medical Costs for the Duke Medical Therapy Group and the Duke Implantable Cardioverter Defibrillator Group
Table Jump PlaceholderTable 5.  Results of Base-Case Analysis
Table Jump PlaceholderTable 6.  Results of One-Way Sensitivity Analysis

References

Zipes DP, Wellens HJ.  Sudden cardiac death. Circulation. 1998; 98:2334-51. PubMed
 
.  A comparison of antiarrhythmic-drug therapy with implantable defibrillators in patients resuscitated from near-fatal ventricular arrhythmias. The Antiarrhythmics versus Implantable Defibrillators (AVID) Investigators. N Engl J Med. 1997; 337:1576-83. PubMed
 
Buxton AE, Lee KL, Fisher JD, Josephson ME, Prystowsky EN, Hafley G.  A randomized study of the prevention of sudden death in patients with coronary artery disease. Multicenter Unsustained Tachycardia Trial Investigators. N Engl J Med. 1999; 341:1882-90. PubMed
 
Moss AJ, Hall WJ, Cannom DS, Daubert JP, Higgins SL, Klein H. et al.  Improved survival with an implanted defibrillator in patients with coronary disease at high risk for ventricular arrhythmia. Multicenter Automatic Defibrillator Implantation Trial Investigators. N Engl J Med. 1996; 335:1933-40. PubMed
 
Moss AJ, Zareba W, Hall WJ, Klein H, Wilber DJ, Cannom DS. et al.  Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. N Engl J Med. 2002; 346:877-83. PubMed
 
Rosati RA, McNeer JF, Starmer CF, Mittler BS, Morris JJ Jr, Wallace AG.  A new information system for medical practice. Arch Intern Med. 1975; 135:1017-24. PubMed
 
Fortin DF, Califf RM, Pryor DB, Mark DB.  The way of the future redux [Editorial]. Am J Cardiol. 1995; 76:1177-82. PubMed
 
Harris PJ, Harrell FE Jr, Lee KL, Behar VS, Rosati RA.  Survival in medically treated coronary artery disease. Circulation. 1979; 60:1259-69. PubMed
 
Califf RM, Harrell FE Jr, Lee KL, Rankin JS, Hlatky MA, Mark DB. et al.  The evolution of medical and surgical therapy for coronary artery disease. A 15-year perspective. JAMA. 1989; 261:2077-86. PubMed
 
Mark DB, Nelson CL, Califf RM, Harrell FE Jr, Lee KL, Jones RH. et al.  Continuing evolution of therapy for coronary artery disease. Initial results from the era of coronary angioplasty. Circulation. 1994; 89:2015-25. PubMed
 
Cox DR.  Regression models and life tables. Journal of the Royal Statistical Society. 1972; 34:187-220.
 
Parmar MK, Torri V, Stewart L.  Extracting summary statistics to perform meta-analyses of the published literature for survival endpoints. Stat Med. 1998; 17:2815-34. PubMed
 
Anderson RN.  A method for constructing complete annual U.S. life tables. Vital Health Stat 2. 2000; (129) 1-28. PubMed
 
Bang H, Tsiatis AA.  Estimating medical costs with censored data. Biometrika. 2000; 87:329-43.
 
Mark DB, Granger CB, Ellis SG, Phillips HR, Knight L, Davidson-Ray L. et al.  Cost of direct angioplasty versus thrombolysis for acute myocardial infarction [Abstract]. Circulation. 1996; 94:168.
 
Eisenstein EL, Shaw LK, Anstrom KJ, Nelson CL, Hakim Z, Hasselblad V. et al.  Assessing the clinical and economic burden of coronary artery disease: 1986-1998. Med Care. 2001; 39:824-35. PubMed
 
Kennergren C.  Impact of implant techniques on complications with current implantable cardioverter-defibrillator systems. Am J Cardiol. 1996; 78:15-20. PubMed
 
.  Medtronic Product Performance Report: Tachyarrhythmia Products. Volume 13. Minneapolis, MN: Medtronic; 2003.
 
Eisenstein EL, Mark DB.  Cost effectiveness of new diagnostic tools and therapies for acute coronary syndromes. Topol EJ Acute Coronary Syndromes. 3rd ed. New York: Marcel Dekker.723-45.
 
Siegel JE, Weinstein MC, Russell LB, Gold MR.  Recommendations for reporting cost-effectiveness analyses. Panel on Cost-Effectiveness in Health and Medicine. JAMA. 1996; 276:1339-41. PubMed
 
Weinstein MC, Siegel JE, Gold MR, Kamlet MS, Russell LB.  Recommendations of the Panel on Cost-effectiveness in Health and Medicine. JAMA. 1996; 276:1253-8. PubMed
 
Tsevat J, Goldman L, Soukup JR, Lamas GA, Connors KF, Chapin CC. et al.  Stability of time-tradeoff utilities in survivors of myocardial infarction. Med Decis Making. 1993; 13:161-5. PubMed
 
Sanders GD, Hlatky MA, Every NR, McDonald KM, Heidenreich PA, Parsons LS. et al.  Potential cost-effectiveness of prophylactic use of the implantable cardioverter defibrillator or amiodarone after myocardial infarction. Ann Intern Med. 2001; 135:870-83. PubMed
 
American Heart Association.  Heart Disease and Stroke Statistics—2003 Update. Dallas, TX: American Heart Assoc; 2002.
 
Spath MA, O'Brien BJ.  Cost effectiveness of implantable cardioverter defibrillator therapy versus drug therapy for patients at high risk of sudden cardiac death. Pharmacoeconomics. 2002; 20:727-38. PubMed
 
Larsen GC, Manolis AS, Sonnenberg FA, Beshansky JR, Estes NA, Pauker SG.  Cost-effectiveness of the implantable cardioverter-defibrillator: effect of improved battery life and comparison with amiodarone therapy. J Am Coll Cardiol. 1992; 19:1323-34. PubMed
 
Kuppermann M, Luce BR, McGovern B, Podrid PJ, Bigger JT Jr, Ruskin JN.  An analysis of the cost effectiveness of the implantable defibrillator. Circulation. 1990; 81:91-100. PubMed
 
Owens DK, Sanders GD, Harris RA, McDonald KM, Heidenreich PA, Dembitzer AD. et al.  Cost-effectiveness of implantable cardioverter defibrillators relative to amiodarone for prevention of sudden cardiac death. Ann Intern Med. 1997; 126:1-12. PubMed
 
Mushlin AI, Hall WJ, Zwanziger J, Gajary E, Andrews M, Marron R. et al.  The cost-effectiveness of automatic implantable cardiac defibrillators: results from MADIT. Multicenter Automatic Defibrillator Implantation Trial. Circulation. 1998; 97:2129-35. PubMed
 
Larsen G, Hallstrom A, McAnulty J, Pinski S, Olarte A, Sullivan S. et al.  Cost-effectiveness of the implantable cardioverter-defibrillator versus antiarrhythmic drugs in survivors of serious ventricular tachyarrhythmias: results of the Antiarrhythmics Versus Implantable Defibrillators (AVID) economic analysis substudy. Circulation. 2002; 105:2049-57. PubMed
 
O'Brien BJ, Connolly SJ, Goeree R, Blackhouse G, Willan A, Yee R. et al.  Cost-effectiveness of the implantable cardioverter-defibrillator: results from the Canadian Implantable Defibrillator Study (CIDS). Circulation. 2001; 103:1416-21. PubMed
 

Letters

NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).

Comments

Submit a Comment
Defibrillators Cost Effective - Only for the Developed West !
Posted on April 27, 2005
Fahim H. Jafary
Aga Khan University Hospital, Karachi, Pakistan
Conflict of Interest: None Declared

We read Al-Khatib et al's [1] article on the cost effectiveness of implantable cardioverter-defibrillators (ICD) in patients meeting the MADIT-II trial criteria with interest. The authors failed to emphasize a major limitation of their study - lack of applicability to over one-third of the world's population living in developing countries. Implantable defibrillators are prohibitively expensive for these nations to even consider. Given that the major contribution to the global burden of cardiovascular disease is anticipated to arise from developing nations [2], it is an unfortunate reality that a large number of deaths that may be prevented by ICD implantation will occur in these countries.

There is an urgent need for cheaper (even if significantly less sophisticated) devices to be marketed to developing nations. Life cannot be regarded as "expendable" no matter which country it pertains to.

References:

1. Sana M. Al-Khatib, Kevin J. Anstrom, Eric L. Eisenstein, Eric D. Peterson, James G. Jollis, Daniel B. Mark, Yun Li, Christopher M. O'Connor, Linda K. Shaw, and Robert M. Califf. Clinical and Economic Implications of the Multicenter Automatic Defibrillator Implantation Trial -II. Ann Intern Med 2005; 142: 593-600

2. Yusuf S, Vaz M, Pais P. Related Articles. Tackling the challenge of cardiovascular disease burden in developing countries. Am Heart J. 2004 Jul;148(1):1-4.

Conflict of Interest:

None declared

Cost Effectiveness of Therapy With Abnormal LV Function Post-MI
Posted on May 2, 2005
William S Weintraub
Emory University
Conflict of Interest: None Declared

Dr. Al-Khatib and colleagues are to be commended for their evaluation of the cost-effectiveness of implantable cardioverter defibrillators (ICD) based on the Multicenter Automatic Defibrillator Implantation Trial-II (MADIT-II).1 At 20 months, mortality was 14.2% in the ICD group and 19.8% in the controls, an absolute difference of 5.6%.2 Cost in the ICD group was estimated at $131,490 and in the medical therapy group $40,661, a difference of $90,829, and a gain in life years of 1.8 years.(1) The authors find ICDs to be marginally cost-effective, with a base-case estimate of the incremental cost-effectiveness ratio (ICER) of $50,500 per life-year gained. Sensitivity analysis suggested that the ICER could vary greatly, from a somewhat lower to a great deal higher value, depending on the assumptions made. The ICER was especially sensitive to the effectiveness of the ICD.

The MADIT-II population is comprised of patients who have had a prior myocardial infarction (MI) and a left ventricular ejection fraction £30%.(2) Patients with prior MI have been shown to benefit from beta- blockade and ACE inhibition. More recently, aldosterone blockade has been shown to be both efficacious and cost-effective.(3,4) In the EPHESUS trial, patients with ejection fraction £40% and evidence of heart failure were randomized to eplerenone or placebo 3-14 days after MI. After a mean duration of 16 months, the absolute difference in survival was 2.3%.(3) Using the Worcester Heart Attack database to project survival, the gain with eplerenone was 0.1337 years. The added cost was $1391, giving an ICER of $10,402 per life-year gained.(4)

It has been shown that ICDs do not reduce overall mortality within the first month post-AMI,(5) nor do they have a favorable effect on any mortality other than arrhythmic death (sudden cardiac death). Eplerenone reduces both all-cause mortality and sudden cardiac death, and starts to do so almost immediately post-MI.(3,6)

Differences in the populations and methods of these two studies make a direct comparison difficult, however it is clear that pharmacotherapy is often more cost-effective than implantable devices or surgical interventions.(7) There is tremendous concern over the cost of pharmacotherapy,(8) which may be due in part to the fact that pharmaceuticals have not been traditionally covered by Medicare. Recent legislation will change that concern in large measure. However, when pharmacotherapy is life-saving and cost-effective, society should be encouraged to make such therapy available to all who need it.

References

1. Al-Khatib SM, Anstrom KJ, Eisenstein EL, et al. Clinical and economic implications of the Multicenter Automatic Defibrillator Implantation Trial-II. Ann Intern Med. 2005;142:593-600.

2. Moss AJ, Zareba W, Hall WJ, et al. Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. N Engl J Med. 2002;346:877-883.

3. Pitt B, Remme W, Zannad F, et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 2003;348:1309-1321.

4. Weintraub WS, Zhang Z, Mahoney EM, et al. Cost-effectiveness of eplerenone compared with placebo in patients with myocardial infarction complicated by left ventricular dysfunction and heart failure. Circulation. 2005;111:1106-1113.

5. Hohnloser SH, Kuck KH, Dorian P, et al, on behalf of the DINAMIT Investigators. Prophylactic use of an implantable cardioverter- defibrillator after acute myocardial infarction. New Engl J Med. 2004;351:2481-2488.

6. Pitt B, White H, Nicolau J, et al on behalf of the EPHESUS Steering Committee. Eplerenone reduces mortality 30 days post- randomization following acute myocardial infarction in patients with left ventricular systolic dysfunction and heart failure. J Am Coll Cardiol. In Press.

7. Winkelmayer WC, Cohen DJ, Berger ML, Neumann PJ. Comparing cost- utility analyses in cardiovascular medicine. In: Weintraub WS, ed. Cardiovascular Health Care Economics. Totowa: Humana Press; 2003;329-356.

8. Weintraub WS, Shine K. Is a paradigm shift in US healthcare reimbursement inevitable? Circulation. 2004;109:1448-1455.

Conflict of Interest:

Grant support from Pfizer

Cost-Effectiveness of ICD therapy
Posted on October 21, 2005
Sana M. Al-Khatib
Duke Clinical Research Institute
Conflict of Interest: None Declared

In Reply: Dr. Weintraub argues that eplerenone, an aldosterone blocker, is more cost-effective than the ICD. Although his estimated incremental cost-effectiveness ratio (ICER) of $10,402 per life-year gained (LYG) for eplerenone seems much more favorable than our base-case ICER of $50,500/LYG for an ICD, we caution against these comparisons when the interventions are not compared head to head.(1) The Multicenter Automatic Defibrillator Implantation Trial-II (MADIT-II) and Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) trials enrolled appreciably different patients. While all patients in EPHESUS had clinical or radiographic evidence of heart failure, half of the patients in MADIT-II did not. While all patients in EPHESUS were 3 to 14 days after myocardial infarction (MI), 88% of patients in MADIT-II had their MI more than 6 months before enrollment in the trial. These differences make comparisons between eplerenone and ICD therapy difficult.(2,3) Another reason to caution against such comparisons is the calculation of ICER is dependent on many assumptions. Unless these assumptions are identical, ICER comparisons are not valid. Among many assumptions, the time horizon, the change of hazard over time, costs of both interventions, and intensity of follow-up visits are important. It is not clear to us what assumptions were used in the ICER calculated by Dr. Weintraub. Based on the results of DINAMIT, Dr. Weintraub states that ICDs do not reduce mortality within the first month post-MI. Although we agree with Dr. Weintraub's interpretation of the DINAMIT trial, we believe this question could not be settled with one clinical trial especially because many more patients in the control group than the ICD group underwent coronary revascularization during the course of DINAMIT.(4) A recent analysis of the Valsartan in Acute Myocardial Infarction Trial (VALIANT) showed the risk of sudden death to be highest in the first 30 days after MI in patients with left ventricular dysfunction, heart failure or both.(5) Thus, whether an ICD is beneficial shortly after an MI, deserves further examination. Notwithstanding the ambiguities in Dr. Weintraub's letter, we agree with him that when pharmacotherapy is life-saving and cost-effective, society should be encouraged to make such therapy available to those who need it. Dr. Jafary brings up a good point regarding the limited access to ICDs in developing countries and the need for cheaper ICDs; however, affordability is a separate issue from cost-effectiveness and it is up to each country to decide how much of its wealth to invest in health care. References 1. Al-Khatib SM, Anstrom K, Eisenstein E, Peterson E, Jollis J, Li Y, O'Connor C, Lee KL, Shaw L, Mark D, Califf RM. Clinical and economic implications of the Multi-center Automatic Defibrillator Implantation Trial II. Ann Int Med. 2005;142:593-600. 2. Moss AJ, Zareba W, Hall WJ, Klein H, Wilber DJ, Cannom DS, et al. Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. The Multicenter Automatic Defibrillator Implantation Trial II Investigators. N Engl J Med. 2002;346:877-83. 3. Pitt B, Remme W, Zannad F, Neaton J, Martinez F, Roniker B, et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. The Eplerenone Post- Acute Myocardial Infarction Heart Failure Efficacy and Survival Study Investigators. N Engl J Med. 2003;348:1309-21. 4. Hohnloser SH, Kuck KH, Dorian P, Roberts RS, Hampton JR, Hatala R, et al. Prophylactic use of an implantable cardioverter-defibrillator after acute myocardial infarction. The DINAMIT Investigators. N Engl J Med. 2004;351:2481-88. 5. Solomon SD, Zelenkofske S, McMurray JJV, Finn PV, Velazquez E, Ertl G, et al. Sudden death in patients with myocardial infarction and left ventricular dysfunction, heart failure, or both. N Engl J Med. 2005;352:2581-8

Conflict of Interest:

I receive research funding from Medtronic and Guidant

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Summary for Patients

What Are the Clinical and Economic Implications of Following MADIT-II Criteria for Surgically Implanting Automatic Cardiac Defibrillators?

The summary below is from the full report titled “Clinical and Economic Implications of the Multicenter Automatic Defibrillator Implantation Trial-II.” It is in the 19 April 2005 issue of Annals of Internal Medicine (volume 142, pages 593-600). The authors are S.M. Al-Khatib, K.J. Anstrom, E.L. Eisenstein, E.D. Peterson, J.G. Jollis, D.B. Mark, Y. Li, C.M. O'Connor, L.K. Shaw, and R.M. Califf.

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