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Meta-analysis: Age and Effectiveness of Prophylactic Implantable Cardioverter-Defibrillators

Pasquale Santangeli, MD; Luigi Di Biase, MD; Antonio Dello Russo, MD; Michela Casella, MD; Stefano Bartoletti, MD; Pietro Santarelli, MD; Gemma Pelargonio, MD; and Andrea Natale, MD
[+] Article and Author Information

From Catholic University of the Sacred Heart, Rome, Italy; St. David's Medical Center and University of Texas, Austin, Texas; University of Foggia, Foggia, Italy; and University of Milan and Istituto Di Ricovero e Cura a Carattere Scientifico, Milan, Italy.


Note: Drs. Santangeli and Di Biase contributed equally to the study and should both be considered as first authors.

Potential Conflicts of Interest: Dr. Di Biase: Consultancy: Hansen Medical. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M10-0999.

Requests for Single Reprints: Pasquale Santangeli, MD, Cardiology Department, Catholic University of the Sacred Heart, Largo A. Gemelli 8, 00168 Rome, Italy; e-mail, pasquale.santangeli@libero.it.

Current Author Addresses: Drs. Santangeli, Bartoletti, Santarelli, and Pelargonio: Cardiology Department, Catholic University of the Sacred Heart, Largo A. Gemelli 8, 00168 Rome, Italy.

Drs. Di Biase and Natale: Texas Cardiac Arrhythmia Institute at St. David's Medical Center, 1015 East 32nd Street, Suite 516, Austin, TX 78705.

Drs. Dello Russo and Casella: Cardiac Arrhythmia Research Center, Monzino Cardiological Center, University of Milan, Via Parea 4, 20038 Milan, Italy.

Author Contributions: Conception and design: P. Santangeli, L. Di Biase, G. Pelargonio, A. Natale.

Analysis and interpretation of the data: P. Santangeli, L. Di Biase, G. Pelargonio.

Drafting of the article: P. Santangeli, L. Di Biase, A. Dello Russo, M. Casella, S. Bartoletti, P. Santarelli, A. Natale.

Critical revision of the article for important intellectual content: L. Di Biase, A. Dello Russo, M. Casella, P. Santarelli, A. Natale.

Final approval of the article: P. Santangeli, L. Di Biase, A. Dello Russo, M. Casella, S. Bartoletti, P. Santarelli, G. Pelargonio, A. Natale.

Statistical expertise: P. Santangeli.

Collection and assembly of data: P. Santangeli, L. Di Biase, G. Pelargonio.


Ann Intern Med. 2010;153(9):592-599. doi:10.7326/0003-4819-153-9-201011020-00009
Text Size: A A A

This article has been corrected. For original version, click "Original Version (PDF)" in column 2.

Background: Implantable cardioverter-defibrillators (ICDs) for the primary prevention of sudden cardiac death have been proven effective in several clinical trials.

Purpose: To summarize evidence about the effectiveness of ICDs versus standard medical therapy for the primary prevention of sudden cardiac death in different age groups of patients with severe left ventricular dysfunction.

Data Sources: MEDLINE, Embase, CENTRAL, BioMed Central, Cardiosource, ClinicalTrials.gov, and ISI Web of Science (January 1970 to April 2010) were searched with no language restrictions.

Study Selection: Two independent reviewers screened titles and abstracts to identify randomized, controlled trials of prophylactic ICD versus medical therapy in patients with severe left ventricular dysfunction that provided data about mortality outcomes for different age groups.

Data Extraction: Two independent reviewers assessed risk for bias of trials and extracted patient and study characteristics and hazard ratios (HRs) relevant to all-cause mortality.

Data Synthesis: Five trials (MADIT-II, DEFINITE, DINAMIT, SCD-HeFT, and IRIS) that enrolled 5783 patients (44% were elderly) were included. The primary analysis, which excluded the 2 trials enrolling patients early after acute myocardial infarction (DINAMIT and IRIS), found that prophylactic ICD therapy reduced mortality in younger patients (HR, 0.65 [95% CI, 0.50 to 0.83]; P < 0.001). A smaller survival benefit was found in elderly patients (HR, 0.75 [95% CI, 0.61 to 0.91]) that was not confirmed when MADIT-II patients older than 70 years were excluded or when data from DINAMIT and IRIS were included.

Limitations: Four potentially eligible trials were not included in the meta-analysis because mortality data by age group were not available. Adjustment for differences in comorbid conditions and medical therapies among patients enrolled in the trials was not possible.

Conclusion: Available data suggest that prophylactic ICD therapy may be less beneficial for elderly patients with severe left ventricular dysfunction than for younger patients.

Primary Funding Source: None.

Figures

Grahic Jump Location
Appendix Figure.
Summary of evidence search and selection.

ICD = implantable cardioverter-defibrillator.

Grahic Jump Location
Grahic Jump Location
Figure 1.
Individual and pooled hazard ratios for all-cause mortality with prophylactic ICD implantation versus standard medical therapy in elderly patients with severe left ventricular dysfunction.

ICD = implantable cardioverter-defibrillator; MI = myocardial infarction. Study acronyms are defined in the Results section. The size of each hazard ratio box indicates the weight from random-effect analysis.

Grahic Jump Location
Grahic Jump Location
Figure 2.
Individual and pooled hazard ratios for all-cause mortality with prophylactic ICD implantation versus standard medical therapy in younger patients with severe left ventricular dysfunction.

ICD = implantable cardioverter-defibrillator; MI = myocardial infarction. Study acronyms are defined in the Results section. The size of each hazard ratio box denotes the weight from random-effect analysis.

Grahic Jump Location

Tables

References

Letters

NOTE:
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Comments

Submit a Comment
Prophylactic Implantable Cardioverter-Defibrillators in the Elderly With Heart Failure
Posted on November 8, 2010
Gen-Min Lin
Hualien-Armed Forces General Hospital, Hualien, Taiwan
Conflict of Interest: None Declared

To the Editor: We read with interest the meta-analysis by Santangeli et al which reported current available data do not conclusively show that prophylactic implantable cardioverter-defibrillator (ICD) therapy improves survival in elderly patients with severe left ventricular dysfunction (1). Apparently, the suboptimal result of prophylactic ICD therapy for the elderly mainly comes from the outcomes of MADIT-II and SCD-HeFT in which the participants with ischemic cardiomyopathy were all in the prior and half in the later (2,3). As we know, the elderly may confer higher risk of death on the events of deteriorated cardiac pump failure, recurrent myocardial infarction, stroke, bleeding and infections in the condition of ischemic cardiomyopathy with antiplatelet therapy than the younger ones. Accordingly, the proportion of cardiac death due to fatal arrhythmia including ventricular tachycardia/ fibrillation and high-degree atrioventricular block that benefits from prophylactic ICD therapy may be attenuated in the elderly with ischemic heart failure. On the contrary, the elderly with nonischemic cardiomyopathy may has less proportion of death resulting from the low incidence of coronary or peripheral vascular events and bleeding that will enhance the effects of prophylactic ICD therapy in this population (4). Therefore, in our opinion, the authors should further separate the populations with severe left ventricular dysfunctions into ischemic- and nonischemic- origins from the collected articles to make some truths behind the meta-analysis become clearer.

Reference

1. Santangeli P, Di Biase L, Dello Russo A, Casella M, Bartoletti S, Santarelli P, Pelargonio G, Natale A. Meta-analysis: Age and Effectiveness of Prophylactic Implantable Cardioverter-Defibrillators. Ann Intern Med. 2010; 153:592-599.

2. Moss AJ, Hall WJ, Cannom DS, Daubert JP, Higgins SL, Klein H, Levine JH, Saksena S, Waldo AL, Wilber D, Brown MW, Heo M. 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; 335:1933-1940.

3. Bardy GH, Lee KL, Mark DB, Poole JE, Packer DL, Boineau R, Domanski M, Troutman C, Anderson J, Johnson G, McNulty SE, Clapp-Channing N, Davidson- Ray LD, Fraulo ES, Fishbein DP, Luceri RM, Ip JH; Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) Investigators. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N Engl J Med. 2005; 352:225-237

4. Kadish A, Dyer A, Daubert JP, Quigg R, Estes NA, Anderson KP, Calkins H, Hoch D, Goldberger J, Shalaby A, Sanders WE, Schaechter A, Levine JH; Defibrillators in Non-Ischemic Cardiomyopathy Treatment Evaluation (DEFINITE) Investigators.Prophylactic defibrillator implantation in patients with nonischemic dilated cardiomyopathy. N Engl J Med. 2004; 350:2151-2158.

Conflict of Interest:

None declared

Re:Prophylactic Implantable Cardioverter-Defibrillators in the Elderly With Heart Failure
Posted on November 23, 2010
Alon Barsheshet
University of Rochester Medical Center, Rochester, NY
Conflict of Interest: None Declared

We have read with great interest the paper of Santangeli and colleagues (1). The authors carried out a meta-analysis evaluating the effectiveness of implantable cardioverter defibrillator (ICD) for primary prevention among young and elderly patients and concluded that available data do not conclusively show that ICD improved survival in elderly patients. We agree with the authors that these findings have important clinical implications and might support that cardiac resyncronization therapy alone may be the best device therapy for elderly (> 65 years) patients with severe left ventricular dysfunction. However, we would like to raise several points that may shed additional light on this meta- analysis findings and implications. This meta-analysis included data on ICD benefit in different age groups without adjusting to clinical characteristics. There are important differences in epidemiology, clinical characteristics, management, and outcome of elderly patients compared with their younger counterparts (2-3), and most importantly, elderly patients have more co-morbidities; Thus, the proportion of patients dying due to ventricular tachyarrhythmia is lower among elderly patients as compared with younger patients. In order to explore the effectiveness of ICD among young and elderly patients it is important to neutralize the effects of co -morbidities by adjusting to clinical variables and/or set as the primary endpoint sudden cardiac death instead of all cause mortality. We have previously shown for MADIT-II patients (4) that after adjustment for multiple clinical variables the beneficial effects of primary ICD implantation in reducing all cause mortality were most prominent among patients 65 to 74 years old (HR 0.63 [0.41-0.95], p=0.03), intermediate among older patients (HR 0.70 [0.41-1.20], p=0.20), and lowest in the younger age group (HR 0.79 [0.48-1.29], p=0.35). These results were stronger for the endpoint of sudden cardiac death, demonstrating a significant benefit for all three age groups (4). In addition, our risk score showing a U-shaped pattern for ICD efficacy comprised 5 clinical risk factors, including age>70 years (5). In conclusion, MADIT-II data have consistently shown that age does not attenuate the benefit of the ICD therapy, but rather the co-morbidities (including impaired renal function, atrial fibrillation, etc.). Therefore, the main implication for clinicians should be to perform appropriate risk assessment prior to ICD implantation regardless of age. The growing number of elderly patients who have left ventricular dysfunction and heart failure warrants a prospective randomized ICD trial in this population.

References

1. Santangeli P, Di Biase L, Dello Russo A, Casella M, Bartoletti S, Santarelli P, et al. Meta-analysis: age and effectiveness of prophylactic implantable cardioverter-defibrillators. Ann Intern Med. 2010;153(9):592- 9.

2. Rich MW. Office management of heart failure in the elderly. Am J Med. 2005;118(4):342-8. 3. Gustafsson F, Torp-Pedersen C, Seibaek M, Burchardt H, Kober L. Effect of age on short and long-term mortality in patients admitted to hospital with congestive heart failure. Eur Heart J. 2004;25(19):1711-7.

4. Goldenberg I, Moss AJ. Treatment of arrhythmias and use of implantable cardioverter-defibrillators to improve survival in elderly patients with cardiac disease. Clin Geriatr Med. 2007;23(1):205-19.

5. Goldenberg I, Vyas AK, Hall WJ, Moss AJ, Wang H, He H, et al. Risk stratification for primary implantation of a cardioverter-defibrillator in patients with ischemic left ventricular dysfunction. J Am Coll Cardiol. 2008;51(3):288-96.

Conflict of Interest:

None declared

Reply to "Prophylactic Implantable Cardioverter-Defibrillators in the Elderly with Heart Failure"
Posted on December 16, 2010
Pasquale Santangeli
Institute of Cardiology, Catholic University of the Sacred Heart, Rome, Italy
Conflict of Interest: None Declared

Dear Editor,

We appreciated the letter by Barsheshet and Goldenberg. We fully agree that comorbidities may play a significant role in determining the survival benefit of prophylactic ICD (1, 2). Accordingly, we clearly stated in the abstract, introduction and discussion of our paper that absence of adjustment for comorbidities may represent a potential limitation of our analysis (2).

We respectfully disagree that MADIT-II subgroup analyses are sufficient to provide consistent evidence that age does not attenuate the benefit of ICD (1). Barsheshet and Goldenberg state that, in the MADIT-II, the benefit of ICD was "most prominent" among patients 65-74 years (P=0.03), "intermediate" among those ?75 years (P=0.20), and "lower" among younger patients (P=0.35). We recognize that there may be a temptation to claim that differences in P values establish differences between subgroups. This argument, although frequently encountered in the medical literature, is incorrect.

Different P values can arise because of differences in treatment effect sizes, in the precision of their estimation, or a combination of the two (3). The process of splitting the primary trial population in different subgroups affects the precision of analyses, and does not allow to draw definite conclusions (3). If we calculate a P for interaction between age subgroups in the MADIT-II, we find a non-significant value of 0.79, which further support the concept that we are dealing with differences in precision of estimates rather than with real differences between subgroups (1).

In addition, age subgroup analyses have not been pre-specified in the original trial (1). Therefore, any reported result is methodologically flawed (3), because if we go on splitting age subgroups long enough we will inevitably find a subgroup in which treatment effect is "significant", and such "significant" result may well be the product of chance alone.

The ISIS-2 trial provides a clear example of how such analyses can be misleading (4). Analyzing the effect of aspirin after acute myocardial infarction according to different birth signs, the authors showed that aspirin was beneficial in all patients except those with the star signs of Libra and Gemini (4, 5).

If we are still administering aspirin to Libra and Gemini post- myocardial infarction patients, we cannot rely only on MADIT-II subgroup analysis to give conclusive recommendations on prophylactic ICD therapy in the elderly.

Only an adequately designed randomized trial of prophylactic device therapy in the elderly will give a definite answer to this relevant issue (2).

References

1. Goldenberg I, Moss AJ. Treatment of arrhythmias and use of implantable cardioverter-defibrillators to improve survival in elderly patients with cardiac disease. Heart Fail Clin. 2007;3(4):519-28.

2. Santangeli P, Di Biase L, Dello Russo A, et al. Meta-analysis: age and effectiveness of prophylactic implantable cardioverter-defibrillators. Ann Intern Med;153(9):592-9.

3. Cochrane Handbook for systematic reviews of interventions, Version 5.0.1. Updated September 2008, The Cochrane Collaboration, 7.7.7.2. available from .

4. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Lancet. 1988;2(8607):349-60.

5. Horton R. From star signs to trial guidelines. Lancet. 2000;355(9209):1033-4.

Conflict of Interest:

None declared

Prophylactic implantable defibrillators in the elderly: accurate background information warranted
Posted on February 8, 2011
Frieder Braunschweig
Karolinska University Hospital, Stockholm, Sweden
Conflict of Interest: None Declared

Dear editor:

Although some studies suggest that patients aged 75 or older derive a similar benefit from primary prophylactic ICD therapy as their younger counterparts [1], considerations to age and non-cardiac comorbidities are critical in the decision to implant a device. The recent meta-analysis by Santangeli and co-workers [2] adds an intriguing observation to the ongoing debate on ICD therapy in the elderly. Based on their primary analysis of three major randomized ICD trials of prophylactic ICD therapy in patients with severe left ventricular dysfunction (DEFINITE, MADIT-II, SCD-HeFT) the authors conclude that the ICD may not improve survival in patients aged 60 to 65 years and above (HR, 0.81 [CI, 0.62 to 1.05]; P= 0.11). This finding has potentially important clinical implications and causes great concern as the reported age cut-off is within the range of average age reported in ICD-trials and below the mean age of ICD patients implanted in clinical routine [3].

However, careful reading of the paper by Sarcangeli et al raises the suspicion that the survival effect of prophylactic ICD treatment in elderly patients has been critically underestimated.

1) According to Table 3 and Figure 1, it appears the mata-analysis merely included MADIT-II patients aged 60-69 years (n=426) while the large group of patients aged 70 and above (n=436) was left out for unclear reasons. Notably, those aged 70 and above had a greater survival benefit from the ICD than those between 60 and 69 years [4]. Therefore, an analysis exclusive of MADIT-II patients ? 70 years would contribute to an underestimation of ICD effects in the elderly.

2) It is not entirely clear how the authors weighted results from the SCD-HeFT trial [5]. While Figure 1 shows the hazard ratio for the comparison of ICD therapy (n=829) with placebo (n=847), the meta-analysis seems to account for all 2521 SCD-HeFT patients (see methods and Table 3), including the 845 patients assigned to amiodarone who are not expected to be part of the present study. In addition, the number of elderly SCD-HEFT patients given in Table 3 is largely exaggerated. Probably, the weight attributed to results from SCD-HeFT has been mistakenly enhanced which, once again, would add to the underestimation of ICD effects on survival in elderly patients.

We concur with the author's call for controlled trials into the matter of implantable device therapies in the elderly. However, we are concerned the present conclusions misjudge actual benefits achieved by ICD implantation and may discourage physicians from recommending a potentially life saving treatment in appropriately selected patients. In fact, a recalculation of the ICD effects on survival among elderly patients included in DEFINITE, MADIT-II and SCD-HeFT may yield a hazard ratio below 0.76 likely to be statistically significant.

References

[1] Huang DT, Sesselberg HW, McNitt S, Noyes K, Andrews ML, Hall WJ, et al. Improved survival associated with prophylactic implantable defibrillators in elderly patients with prior myocardial infarction and depressed ventricular function: a MADIT-II substudy. J Cardiovasc Electrophysiol. 2007;18:833-8.

[2] Santangeli P, Di Biase L, Dello Russo A, Casella M, Bartoletti S, Santarelli P, et al. Meta-analysis: age and effectiveness of prophylactic implantable cardioverter-defibrillators. Ann Intern Med. 2010;153:592-9.

[3] Epstein AE, Kay GN, Plumb VJ, McElderry HT, Doppalapudi H, Yamada T, et al. Implantable cardioverter-defibrillator prescription in the elderly. Heart Rhythm. 2009;6:1136-43.

[4] 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.

[5] Bardy GH, Lee KL, Mark DB, Poole JE, Packer DL, Boineau R, et al. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N Engl J Med. 2005;352:225-37.

Conflict of Interest:

None declared

Author's response
Posted on March 30, 2011
Pasquale Santangeli
Texas Cardiac Arrhythmia Institute, St. David's Medical Center, Austin (TX)
Conflict of Interest: None Declared
In response to Drs. Braunschweig and Wedel, the authors have modified the inclusion criteria by including the MADIT II population above 70 years of age. In this way a small ICD survival benefit in the elderly was detected (HR, 0.75 [CI, 0.61 to 0.91]; number needed to treat = 24 [95% CI 16 to 67]). However, the authors wish to clarify that such benefit was entirely driven by the inclusion of MADIT-II patients >70 years, who constituted a minority (436/2414, 18%) of the elderly population included in the meta-analysis, and was not confirmed by repeated analyses excluding this subgroup or including data from the DINAMIT and IRIS. Moreover, the analysis of the upper 95% confidence interval limit of the number needed to treat in the elderly (i.e., 67 ICDs needed to be implanted to prevent one death over 2 years) questions whether the mortality benefit of prophylactic ICDs in this subgroup is conclusive and cost-effective.In younger patients the number needed to treat was 17 (95% CI 12 to 35) and the benefit remained significant after all the pre-specified sensitivity analyses.
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