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; Robert M. Califf, MD
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.
The Multicenter Automatic Defibrillator Implantation Trial (MADIT)-II demonstrated that implantable cardioverter defibrillators (ICDs) save lives when used in patients with a history of myocardial infarction (MI) and an ejection fraction of 0.3 or less.
To investigate the cost-effectiveness of implanting ICDs in patients who met MADIT-II eligibility criteria and were enrolled in the Duke Cardiovascular Database between 1 January 1986 and 31 December 2001.
Published literature, databases owned by Duke University Medical Center, and Medicare data.
Adults with a history of MI and an ejection fraction of 0.3 or less.
ICD therapy versus conventional medical therapy.
Cost per life-year gained and incremental cost-effectiveness.
Compared with conventional medical therapy, ICDs are projected to result in an increase of 1.80 discounted years in life expectancy and an incremental cost-effectiveness ratio of $50 500 per life-year gained. 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. 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.
The study was limited by the completeness of the data, referral bias, difference in medical therapy between the Duke cohort and the MADIT-II cohort, and not addressing potential upgrades to biventricular devices.
The economic expense of defibrillator implantation in all patients who meet MADIT-II eligibility criteria is substantial. However, in the range of survival benefit observed in MADIT-II, ICD therapy for these patients is economically attractive by conventional standards.
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.
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.
The large number of patients eligible for ICDs under MADIT-II criteria may strain societal ability to perform and pay for these procedures.
Table 1. Comparison of Baseline Clinical Characteristics of the Duke Medical Therapy Group and Patients in the Multicenter Automatic Defibrillator Implantation Trial-II
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.
Survival projections for implantable cardioverter defibrillator (ICD) therapy versus medical therapy.
Table 2. Clinical Events, Survival, and Medical Costs for the Duke Medical Therapy Group
Table 3. Costs for Placement of Implantable Cardioverter Defibrillators, Follow-up, Maintenance, and Complications
Table 4. Projected Survival and Medical Costs for the Duke Medical Therapy Group and the Duke Implantable Cardioverter Defibrillator Group
Table 5. Results of Base-Case Analysis
Table 6. Results of One-Way Sensitivity Analysis
Cost-effectiveness of implantable cardioverter defibrillator (ICD) therapy versus medical therapy.
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Fahim H. Jafary
Aga Khan University Hospital, Karachi, Pakistan
April 27, 2005
Defibrillators Cost Effective - Only for the Developed West !
We read Al-Khatib et al's  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 , 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.
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.
William S Weintraub
May 2, 2005
Cost Effectiveness of Therapy With Abnormal LV Function Post-MI
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 Â£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 Â£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.
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.
Grant support from Pfizer
Sana M. Al-Khatib
Duke Clinical Research Institute
October 21, 2005
Cost-Effectiveness of ICD therapy
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
I receive research funding from Medtronic and Guidant
Al-Khatib SM, Anstrom KJ, Eisenstein EL, Peterson ED, Jollis JG, Mark DB, et al. Clinical and Economic Implications of the Multicenter Automatic Defibrillator Implantation Trial-II. Ann Intern Med. ;142:593–600. doi: 10.7326/0003-4819-142-8-200504190-00007
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Published: Ann Intern Med. 2005;142(8):593-600.
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