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Review Annals of Internal Medicine Systematic Review: Implantable Cardioverter Defibrillators for Adults with Left Ventricular Systolic Dysfunction Justin A. Ezekowitz, MB, BCh, MSc; Brian H. Rowe, MD, MSc; Donna M. Dryden, PhD; Nicola Hooton, MPH; Ben Vandermeer, MSc; Carol Spooner, BScN, MSc; and Finlay A. McAlister, MD, MSc Background: Patients with left ventricular (LV) systolic dysfunction have an increased risk for ventricular arrhythmias. Purpose: To summarize the evidence about benefits and harms of implantable cardioverter defibrillators (ICDs) in adult patients with LV systolic dysfunction. Data Sources: A search of electronic databases (including MEDLINE, EMBASE, Cochrane Central, and U.S. Food and Drug Administration reports) from 1980 through April 2007, not limited by language of publication, was supplemented by hand searches and contact with study authors and device manufacturers. Study Selection: Two reviewers independently selected studies on the basis of prespecified criteria. They selected 12 randomized, controlled trials (RCTs) (8516 patients) that reported on mortality and 76 observational studies (96 951 patients) that examined safety or effectiveness. ICDs reduced all-cause mortality by 20% (95% CI, 10% to 29%) in the RCTs and by 46% (CI, 32% to 57%) in the observational studies. Death associated with implantation of ICDs occurred during 1.2% (CI, 0.9% to 1.5%) of procedures. The frequency of postimplantation complications per 100 patient-years included 1.4 (CI, 1.2 to 1.6) device malfunctions, 1.5 (CI, 1.3 to 1.8) lead problems, and 0.6 (CI, 0.5 to 0.8) site infection. Rates of inappropriate discharges per 100 patient-years ranged from 19.1 (CI, 16.5 to 22.0) in RCTs to 4.9 (CI, 4.5 to 5.3) in observational studies. Limitations: Studies were of short duration and infrequently reported nonfatal outcomes. Few studies evaluated dual-chamber ICDs. Lack of individual-patient data prevents identification of subgroup-specific effects. Data Extraction: Data were extracted in duplicate and independently by 2 reviewers. Conclusions: Implantable cardioverter defibrillators are efficacious in reducing mortality for adult patients with LV systolic dysfunction, and this benefit extends to nontrial populations. Improved risk stratification tools to identify patients who are most likely to benefit from ICD are needed. Data Synthesis: In adult patients with LV systolic dysfunction, 86% of whom had New York Heart Association class II or III symptoms, Ann Intern Med. 2007;147:251-262. For author affiliations, see end of text. L effectiveness (that is, the risks and benefits of a therapy when tested under usual clinical practice conditions) and safety of ICDs when used in clinical practice. eft ventricular (LV) systolic dysfunction carries a high risk for sudden cardiac death (1). Implantable cardioverter defibrillators (ICDs) can potentially mitigate this risk by delivering rapid life-saving therapy and have been substantially refined since their initial development in the late 1970s (2). Randomized, controlled trials (RCTs) have tested the efficacy of ICDs in high-risk individuals. We previously reported a systematic review of 8 RCTs (3 RCTs of secondary prevention in survivors of sudden cardiac death; 5 RCTs of primary prevention in patients without a history of ventricular arrhythmias) demonstrating a 26% reduction in all-cause mortality and a 57% reduction in sudden cardiac death with ICDs (3). Since then, additional RCTs of primary prevention have been published, and questions have arisen about the generalizability of the RCT results for ICDs to clinical practice. In particular, it is uncertain whether the benefits of ICDs seen in the trials extend to nontrial populations and whether the risks associated with ICDs may be higher in clinical practice than reported in trials. Given the public policy implications, we extended our previous systematic review of the efficacy (that is, the risks and benefits of a therapy when tested under ideal circumstances) (4) of ICDs in patients with LV systolic dysfunction by updating it with recently published RCTs that examined efficacy. In addition, we expanded the review to include data from observational studies to determine the www.annals.org METHODS A study protocol meeting Cochrane criteria, including all of the elements described briefly in the following sections, was developed and followed by the study authors in conjunction with the Agency for Healthcare Research and Quality (AHRQ). Search Strategy We sought studies published between 1980 and 27 April 2007 by searching MEDLINE, Ovid MEDLINE InProcess & Other Non-Indexed Citations, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of See also: Web-Only Appendix Tables CME quiz Conversion of figures and tables into slides Audio summary © 2007 American College of Physicians 251 Review Implantable Cardioverter Defibrillators for Left Ventricular Systolic Dysfunction Figure 1. Flow diagram of study identification and selection. implantation complications with ICDs in adult patients with LV systolic dysfunction (left ventricular ejection fraction [LVEF] ⱕ0.35, regardless of whether the patients had heart failure symptoms). To address efficacy questions, we restricted the analyses to RCTs. To address effectiveness questions, we expanded our inclusion criteria to include observational studies with contemporaneous comparison groups (such as cohort studies) and RCTs that did not report efficacy outcomes. To address safety questions, we included evidence from both RCTs and observational studies (including those without contemporaneous control groups, such as case series and registry data). Data Extraction and Analysis RCT ⫽ randomized, controlled trial. Effects, Health Technology Assessment Database, EMBASE, Science Citation Index Expanded (via Web of Science), International Pharmaceutical Abstracts, PubMed, National Library of Medicine Gateway, OCLC ProceedingsFirst and PapersFirst, Computer Retrieval of Information on Scientific Projects, various trial registries (including the National Research Register [United Kingdom], Australian Clinical Trials Registry, ClinicalTrials.gov, and Current Controlled Trials), and U.S. Food and Drug Administration reports. In addition, we hand-searched abstracts from the annual Heart Rhythm Society meetings and the reference lists of review articles and included studies; we also contacted authors of included studies for additional citations and information. Unpublished studies and individual-patient data were sought from device manufacturers, including Medtronic (Minneapolis, Minnesota), Guidant Corp. (Indianapolis, Indiana), and St. Jude Medical (St. Paul, Minnesota). The search was not limited by language or publication status. The search terms included MedtronicInSync, ELA medical, Guidant, St. Jude, implantable defibrillators, implantable cardioverter defibrillators, AICD, ICD, single chamber ICD, dual chamber ICD, congestive heart failure, CHF, chronic heart failure, and heart diseases. A full list of search strategies (adapted for each database) and search results are available at www.ahrq.gov/clinic/tp/defibtp.htm (5). Study Selection We selected original research studies that had at least 25 participants and reported mortality or peri- or post252 21 August 2007 Annals of Internal Medicine Volume 147 • Number 4 Study selection, quality assessment, and data extraction were completed by several investigators in duplicate and independently, using the methods recommended by the Quality of Reporting of Meta-analyses (QUOROM) group (6). We assessed quality by using the methods of Schulz and colleagues (7), the 5-item Jadad scale (8), and the 27-point Downs and Black scale (9). Publication bias was assessed visually by using funnel plots and quantitatively by using the rank correlation test (10), the graphical test (11), and the trim-and-fill method (12). Randomeffects models were used to calculate pooled relative risks (RRs) in Review Manager 4.2.5 (Cochrane Collaboration, Copenhagen, Denmark). The length of study follow-up versus all-cause mortality was plotted for each study, and inverse variance–weighted least-squares regression was used to create a best-fit line. Postimplantation complications were expressed per 100 patient-years (calculated by multiplying the frequency of events in each study by the duration of follow-up, and standardizing to a denominator of 100) and are unadjusted rates. All results were reported with 95% CIs and, where appropriate, SDs or SEs. Statistical heterogeneity was quantified by using the I2 statistic (13). In addition to examining for differences in point estimates across study designs and study quality, we explored device efficacy in different patient subgroups by using meta-regression. Covariates tested included presence of cardiac resynchronization therapy, length of follow-up, ischemic etiology, New York Heart Association (NYHA) class, age, QRS interval, LVEF, and primary versus secondary prevention. Role of the Funding Source The funding source (AHRQ, U.S. Department of Health and Human Services) had no role in the collection, analysis, or interpretation of the data or in the decision to submit the manuscript for publication. RESULTS Literature Search From 4439 citations (Figure 1), we identified 12 RCTs (8516 patients) for the ICD efficacy review (14 – 26), 53 studies (26 840 patients from 5 nonefficacy RCTs www.annals.org Implantable Cardioverter Defibrillators for Left Ventricular Systolic Dysfunction and 48 observational studies [25 retrospective and 23 prospective]) for the ICD effectiveness review (27–78), and 64 studies (86 809 patients from 11 efficacy RCTs, 10 RCTs without efficacy outcomes, and 43 observational studies [24 retrospective and 19 prospective]) for the ICD safety review (14 –17, 19 –27, 29, 30, 34, 37– 40, 42– 45, 47, 48, 52, 54, 60, 61, 63– 66, 69, 70, 72–75, 78 –101). A full list of search strategies, search results, detailed quality assessments for each included study, and tests for publication bias are available at www.ahrq.gov/clinic/tp/defibtp.htm (5). No publication bias was seen on the funnel plots. RCTs with Efficacy Data The 12 efficacy RCTs varied in quality (ranging from 1 to 3 on the Jadad scale) and duration (ranging from 15 to 66 months). All but 2 trials (16, 19) evaluated singlechamber ICDs (although no trials reported protocol adherence to single-chamber vs. dual-chamber ICDs). All patients in the RCTs had LV systolic dysfunction: Mean LVEF ranged from 0.21 to 0.28 in the primary prevention trials and from 0.32 to 0.46 in the secondary prevention trials. Most patients also had symptoms of heart failure: Review 50% had NYHA class II symptoms at baseline; 36%, class III symptoms; and 3%, class IV symptoms. Eleven percent of trial participants were in NYHA class I at baseline (Appendix Table 1, available at www.annals.org). The mean age of RCT participants was 61 years (SD, 4), 74% were male, and 59% had ischemic heart disease. Use of ICDs reduced all-cause mortality in patients with LV systolic dysfunction by 20% (95% CI, 10% to 29%; I2 ⫽ 44.4%) (Figure 2), largely because of a 54% relative reduction (CI, 37% to 63%; I2 ⫽ 0%) in sudden cardiac deaths. In patients with LV systolic dysfunction, ICDs were equally beneficial in reducing all-cause mortality in both primary prevention trials (RR, 0.81 [CI, 0.69 to 0.95]; I2 ⫽ 53.1% across 9 RCTs) and secondary prevention trials (RR, 0.77 [CI, 0.65 to 0.91]; I2 ⫽ 13.2% across 3 RCTs) (P for this indirect comparison ⫽ 0.56). A single trial included cardiac resynchronization therapy in both study groups for its comparison of ICDs versus control (19). All-cause mortality (RR, 0.83 [CI, 0.66 to 1.05]) was similar to that reported from the remainder of the studies, which did not contain cardiac resynchroniza- Figure 2. Effect of implantable cardioverter defibrillator (ICDs) on all-cause mortality in randomized trials. AMIOVIRT ⫽ Amiodarone vs. Implantable Defibrillator Randomized Trial; AVID ⫽ Antiarrhythmics Versus Defibrillators; CABG Patch ⫽ Coronary Artery Bypass Graft Patch Trial; CASH ⫽ Cardiac Arrest Study Hamburg; CAT ⫽ Cardiomyopathy Trial; CIDS ⫽ Canadian Implantable Defibrillator Study; COMPANION ⫽ Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure Trial; DEFINITE ⫽ Defibrillators in NonIschemic Cardiomyopathy Treatment Evaluation; DINAMIT ⫽ Defibrillator in Acute Myocardial Infarction Trial; MADIT ⫽ Multicenter Automatic Defibrillator Implantation Trial; RR ⫽ relative risk; SCD-HeFT ⫽ Sudden Cardiac Death in Heart Failure Trial. www.annals.org 21 August 2007 Annals of Internal Medicine Volume 147 • Number 4 253 Review Implantable Cardioverter Defibrillators for Left Ventricular Systolic Dysfunction Figure 3. Effect of implantable cardioverter defibrillators (ICDs) on all-cause mortality in observational studies with contemporaneous control groups. MUSTT ⫽ Multicenter Unsustained Tachycardia Trial; RR ⫽ relative risk. tion therapy in either study group (RR, 0.79 [CI, 0.69 to 0.91]) (P for indirect comparison ⫽ 0.92). Only 1 trial reported a statistically significant difference in the effect of ICDs across NYHA classes: The mortality benefits were greater in patients with NYHA class II symptoms than in those with NYHA class III symptoms in the Sudden Cardiac Death in Heart Failure Trial (P ⬍ 0.001 for interaction term of NYHA class and mortality) (22). In a series of univariate meta-regression sensitivity analyses, none of the covariates we examined (duration of follow-up, primary vs. secondary prevention, ischemic cause, presence of cardiac resynchronization therapy, NYHA class, mean age, mean LVEF, or mean QRS duration) contributed to the moderate statistical heterogeneity observed in our meta-analysis of all-cause mortality. In addition, our estimate of treatment effect was not associated with study quality. Implantable cardioverter defibrillators did not seem to be associated with an increase in symptoms of heart failure or deteriorations in functional status or quality of life in RCT participants; however, these outcomes were infrequently reported (see full AHRQ report for details [5]). For example, hospitalizations for heart failure were reported in only 2 trials (pooled RR, 1.1 [CI, 0.76 to 1.59]). Observational Studies and Trials with Effectiveness Data The 47 cohort studies, 5 nonefficacy RCTs, and 1 case– control study varied in quality (ranging from 7 to 28 on the Downs and Black scale) and duration (median, 29 months [interquartile range, 19 to 37 months]). All studies enrolled similar patient populations. Twenty of the 53 254 21 August 2007 Annals of Internal Medicine Volume 147 • Number 4 studies reported the type of ICD implanted: 18 studies included patients receiving both single- and dual-chamber ICDs, 1 study included those receiving dual-chamber ICDs only, and 1 study included those receiving singlechamber ICDs only. Fifteen of these studies evaluated ICDs for primary prevention, 4 reported ICD data for secondary prevention, 30 reported on a mix of primary and secondary prevention patients, and 4 studies were unclear. All patients in these studies (Appendix Table 2, available at www.annals.org) had LV systolic dysfunction (mean LVEF ranged from 0.19 to 0.46), and most had symptoms of heart failure (32% were in NYHA class II, 40% were in class III, and 5% were in class IV). Demographic characteristics were similar to those of participants in the RCTs of ICD efficacy: The mean age was 63 years (SD, 13), 82% of patients were male, and 67% had underlying ischemic heart disease. The pooled effectiveness estimate from the controlled observational studies suggested a greater benefit from ICDs on all-cause mortality (RR, 0.54 [CI, 0.43 to 0.68]) than had been seen in the RCTs (Figure 3), but with greater heterogeneity between studies (I2 ⫽ 60.4%). The observational studies demonstrated a reduced frequency of noncardiac death in ICD recipients (RR, 0.74 [CI, 0.65 to 0.85] in 8 studies with 8759 patients; I2 ⫽ 0%). We evaluated the effect of quality (via meta-regression) on all-cause mortality. Contrary to expectations, higher-quality studies reported a greater benefit from ICDs, but this finding was not significant (P ⫽ 0.09). As shown in Figure 4, mortality over time was similar in ICD recipients enrolled in RCTs www.annals.org Implantable Cardioverter Defibrillators for Left Ventricular Systolic Dysfunction and in observational studies (both prospective and retrospective). Observational Studies and Trials with Harms Data In 53 studies (Appendix Table 2, available at www .annals.org) enrolling patients with LV systolic dysfunction only (median LVEF, 0.31), rate of success of ICD implantation was 99% (CI, 98.8% to 99.3%) and peri-implantation deaths occurred in 1.2% (CI, 0.9% to 1.5%) of procedures. These studies varied in quality (ranging from 18 to 27 on the Downs and Black scale) and duration (median, 28 months [interquartile range, 19 to 48 months]) but enrolled similar patient populations. In 24 studies, patients received either a dual- or a single-chamber ICD; in 4 studies, patients received dual-chamber ICDs only; and in 10 studies, patients received single-chamber ICDs only. The remaining studies did not report the type of device. The frequency of postimplantation complications (per 100 patient-years) included 1.4 (CI, 1.2 to 1.6) device malfunctions, 1.5 (CI, 1.3 to 1.8) lead problems, and 0.6 (CI, 0.5 to 0.8) implant site infection. The rate of inappropriate discharges per 100 patient-years was 19.1 (CI, 16.5 to 22.0) in the RCTs and 4.9 (CI, 4.5 to 5.3) in the observational studies (Table 1). We also examined peri-implantation deaths and success rates in 12 studies (68 848 patients) that enrolled all patients undergoing ICD implantation (that is, not just those patients with LV systolic dysfunction: 1 study of primary prevention, 3 studies of secondary prevention, 7 studies of both, and 1 study unclear) (90 –101). The proportions were similar to those reported in the studies restricted to patients with LV systolic dysfunction: The implantation success rate was 98.6% (CI, 98.3% to 98.9%), and peri-implantation deaths occurred during 1.3% (CI, 1.2% to 1.4%) of procedures. DISCUSSION This systematic review examined the efficacy, effectiveness, and safety of ICDs in adult patients with LV dysfunction. The results confirm that ICDs reduce the relative risk for death by 20% for adults who have an LVEF of 0.35 or less and predominantly NYHA class II and III symptoms. This effect exists regardless of whether a patient has a history of hemodynamically apparent ventricular arrhythmias or an ischemic cause. Our review goes beyond previous reviews of this topic in demonstrating that 1) the survival benefits of ICDs extend beyond the RCT setting and 2) the implantation success rate and safety of ICDs are similar in clinical practice and RCTs. The fact that the controlled observational studies demonstrated a reduced frequency of noncardiac death in ICD recipients suggests that clinicians select healthier patients for ICD insertion, and this probably accounts for the larger apparent benefit from ICDs on all-cause mortality in observational studies than in RCTs. However, our data on patient and device-related complication rates highlight the perhaps underappreciated risks www.annals.org Review of ICDs, particularly in light of 3 findings. First, three quarters to two thirds of ICD recipients in the observational studies received no therapeutic ICD discharges, and only 5% to 12% of trial participants received an appropriate shock per year (102). Second, the frequency of inappropriate shocks was surprisingly high, and at least 1 study has demonstrated that inappropriate shocks are associated with an increase in risk for death (hazard ratio, 1.97 [CI, 1.29 to 3.01] in the Sudden Cardiac Death in Heart Failure Trial) (103). Third, although the studies we reviewed infrequently report quality-of-life outcomes, some studies have shown that quality of life declines in many ICD recipients (104), especially those who experience frequent ICD firings (105, 106). Not unexpectedly, patient anxiety and psychological distress scores increase substantially after an ICD shock (107) or after publicity about device recalls (108). Thus, whereas the Multicenter Automatic Defibrillator Implantation Trial II and Sudden Cardiac Death in Heart Failure Trial eligibility criteria are commonly cited as a way to identify patients who might benefit from an ICD, the development and validation of risk stratification tools (such as microvolt T-wave alternans [109] or elevated natriuretic peptide levels [110]) to identify patients who are most likely to benefit from an ICD are vitally important (111, 112). This is particularly true because less than one quarter of patients with cardiac arrest have an LVEF less than 0.30 before the event (113). Although our metaregressions did not reveal any patient subgroups who were statistically more or less likely to benefit from an ICD, we should emphasize that these analyses were post hoc and underpowered because of the small number of RCTs. A Figure 4. Scatter plot of all-cause mortality versus length of follow-up for recipients of implantable cardioverter defibrillators who were enrolled in different types of studies. Circle ⫽ prospective cohort study; square ⫽ randomized, controlled trial; triangle ⫽ retrospective cohort study. Size of plotting character is proportional to the square root of the sample size of study. 21 August 2007 Annals of Internal Medicine Volume 147 • Number 4 255 Review Implantable Cardioverter Defibrillators for Left Ventricular Systolic Dysfunction Table 1. Peri- and Postimplantation Risks of Implantation of Cardioverter Defibrillators* Outcome Peri-implantation complications Death Implantation success rate Mechanical complication Postimplantation complications Mechanical malfunction Device malfunction Lead problems Infections Inappropriate shocks Type of Study Studies, n Raw Data† Pooled Risk Estimates (95% CI)‡ RCT (LVSD) RCT (non-LVSD) Observational (LVSD) Observational (non-LVSD) Total RCT (LVSD) RCT (non-LVSD) Observational (LVSD) Observational (non-LVSD) Total RCT Observational studies Total 8 4 20 6 38 10 4 14 3 31 5 13 18 35/2014 0/725 24/2888 454/34 231 513/39 858 3657/3716 766/777 2473/2473 4107/4163 11 003/11 129 88/1740 88/1559 176/3299 1.7 (1.2–2.4) 0.0 (0.0–0.4) 0.8 (0.5–1.2) 1.3 (1.2–1.5) 1.3 (1.2–1.4) 98.4 (98.0–98.8) 98.6 (97.5–99.3) 100.0 (99.9–100.0) 98.7 (98.3–99.0) 98.9 (98.7–99.1) 5.1 (4.1–6.2) 5.6 (4.6–6.9) 5.3 (4.6–6.2) RCT Observational Total RCT Observational Total RCT Observational Total RCT Observational Total RCT Observational Total 3 6 9 5 5 10 6 10 16 8 9 17 2 27 29 11/1477 33/5478 44/6955 91/6429 57/4436 148/10 865 38/2303 123/6354 161/10 527 58/1232 18/7037 76/12 436 155/810 556/11 448 711/12 258 0.7 (0.4–1.3) 0.6 (0.4–0.8) 0.6 (0.5–0.8) 1.4 (1.1–1.7) 1.3 (1.0–1.7) 1.4 (1.2–1.6) 0.9 (0.6–1.2) 1.9 (1.6–2.3) 1.5 (1.3–1.8) 1.1 (0.8–1.4) 0.3 (0.2–0.4) 0.6 (0.5–0.8) 19.1 (16.5–22.0) 4.9 (4.5–5.3) 5.8 (5.4–6.2) * LVSD ⫽ studies restricted to patients with left ventricular systolic dysfunction; non-LVSD ⫽ studies of all persons receiving an implantable cardioverter defibrillator; RCT ⫽ randomized, controlled trial. † Data for peri-implantation complications are expressed as the number per attempted procedure. Data for postimplantation complications are expressed as the number of patients/patient-years. ‡ Risk estimates for peri-implantation complications are expressed as percentages. Risk estimates for postimplantation complications are expressed per 100 patient-years. meta-analysis of individual-patient data would be necessary to more thoroughly examine this issue. Indeed, the establishment of the ICD Registry by the American College of Cardiology National Cardiovascular Data Registry (ACCNCDR) in conjunction with the Heart Rhythm Society is an important initiative that will permit the collection of comprehensive data on ICD implantations and long-term outcomes. These efforts should help to identify whether particular patient subgroups derive more or less benefit and whether specific devices or particular programming variables are associated with improved outcomes (114). Regardless, the current evidence base does provide some guidance in the selection of candidates for a primary prevention ICD. For example, because ICDs were not associated with mortality benefits when implanted at the time of bypass surgery (15), within 40 days of a myocardial infarction (21), or within 6 months of coronary revascularization (hazard ratio, 1.19; P ⫽ 0.76) (115), the recommendation in the American College of Cardiology/American Heart Association/European Society of Cardiology 2006 guidelines (116) to delay ICD implantation after acute coronary events or coronary revascularization is ap256 21 August 2007 Annals of Internal Medicine Volume 147 • Number 4 propriate. Reports that ICD recipients with a baseline QRS interval of 120 ms or greater are at increased risk for subsequent heart failure (117) highlight a subgroup of ICDeligible patients (those with NYHA III symptoms, LVEF ⱕ0.35, and QRS interval ⱖ120 ms) who should be considered for a combined cardiac resynchronization therapy–ICD device per the recommendations of the American Heart Association, American College of Cardiology, and Heart Rhythm Society (116). Our analysis is limited by a paucity of data on dualchamber ICDs. While 1 study reported a 47% improvement in the odds of detecting supraventricular tachycardia and averting potentially inappropriate ICD therapy (81) with a dual-chamber ICD, 3 observational studies (118 – 120) and 1 small RCT (87) failed to show benefit with dual-chamber ICDs over single-chamber ICDs. Indeed, the largest RCT to date has suggested that dual-chamber ICDs may exacerbate heart failure in patients without an indication for dual-chamber pacing (121). In addition, a post hoc analysis of the Multicenter Automatic Defibrillator Implantation Trial II demonstrated a higher risk for death or heart failure hospitalization among patients who www.annals.org Implantable Cardioverter Defibrillators for Left Ventricular Systolic Dysfunction received a dual-chamber ICD than among those who received a single-chamber ICD (122). Because the choice of single- versus dual-chamber ICDs was not randomized, this subgroup comparison may be biased. For example, patients who received dual-chamber devices were older, had more advanced heart failure symptoms, and had more comorbid conditions; thus, after multivariable adjustment, the excess risks with dual-chamber ICDs were not statistically significant (hazard ratio for death, 1.27 [CI, 0.76 to 2.12]; hazard ratio for heart failure hospitalization, 1.27 [CI, 0.87 to 1.86]). An unpublished RCT (the Dual Chamber and Atrial Tachyarrhythmias Adverse Events Study) (123), which used different device settings with a longer atrioventricular delay, reported fewer inappropriate shocks with dual-chamber ICDs than with standard singlelead ICDs. Thus, dual-chamber ICDs must be tested against single-chamber ICDs in an appropriately powered RCT before definitive conclusions can be drawn about which device to use. In the meantime, although the most recent guidelines for ICDs and the prevention of sudden cardiac death are silent on the indications for dual-chamber devices (116), we believe it prudent to restrict the use of dual-chamber ICDs to patients who require an ICD and have conventional indications for dual-chamber pacing (such as chronotropic incompetence, the sick sinus syndrome, or atrioventricular conduction abnormalities) (124). While we report on patient and device-related complication rates in this review, it should be recognized that it is difficult to estimate the true incidence of ICD device failure. The observed failure rates are probably underestimated because of the tendency to attribute patient deaths to the underlying disease process rather than unrecognized device malfunction. Indeed, an analysis of U.S. Food and Drug Review Administration Enforcement Reports over the past decade demonstrated marked increases in device recall rates over time (as devices have become smaller and more complicated). Currently, ICD recall rates are as high as 16.4 per 100 person-years—54% for hardware malfunctions (electrical or circuitry malfunctions, battery or capacitor malfunctions, problems with hermetic seals, defective crystals, and defective headers) and 41% for firmware malfunctions (integral device computer programming) (125). The cost-effectiveness of ICDs in patients with LV dysfunction has been analyzed several times. Results have varied (126 –129); however, no study has accounted for ICD advisories and replacements, which increased total health care costs by as much as $90 million per year (125). Since variability in model estimates is due in part to uncertainty about complication rates, our data should strengthen the assumptions upon which these analyses are based. Accounting for these new data and observations should be a priority for all future analyses of ICD cost. Our systematic review has a few limitations that deserve consideration, some of which were identified in previous reviews (130). The conclusions of a systematic review are limited by available data; we sought to minimize this by an extensive search that included gray literature and U.S. Food and Drug Administration reports. We could not obtain individual-patient data to explore the subgroups that get more or less benefit from an ICD; however, we performed meta-regression by using aggregate trial-level data, which did not reveal variation across the variables we tested. Because of incomplete reporting of outcomes in the selected studies, certain device-related issues cannot be explored, such as benefits and safety of dual-chamber versus single-chamber devices, even within an RCT. In the obser- Table 2. Summary of Evidence for Implantable Cardioverter Defibrillators in Patients with Left Ventricular Systolic Dysfunction* Symptom Status Quality of Evidence Magnitude of Effect (95% CI)† Conclusion History of ventricular fibrillation or tachycardia NYHA class II or III High (many RCTs with homogeneous results) High (many RCTs with homogeneous results) Definite benefit Definite benefit NYHA class I Low (post hoc metaregression using aggregate trial data from 12 RCTs) Primary prevention in NYHA class IV Moderate (within-RCT comparison, but not primary aim of RCT; in addition, study used post hoc metaregression with aggregate trial data from 12 RCTs) Reduced mortality: 0.77 (0.65–0.91) Reduced mortality: 0.81 (0.69–0.95) No significant effect on hospitalizations for heart failure: 1.10 (0.76–1.59) No significant association in meta-regression between proportion of patients with class I symptoms and reduction in mortality (P ⫽ 0.13) Mortality hazard ratio, 1.27 (0.68–2.37), in CRT-ICD group vs. CRT-alone group among patients with class IV symptoms in COMPANION, but no significant association in metaregression between proportion of patients with class IV symptoms and reduction in mortality (P ⫽ 0.62) Inconclusive Inconclusive * Other considerations may outweigh the trial evidence in some situations (e.g., the patient who wishes to have a do-not-resuscitate order), and there are no data on the effects of ICDs in patients with advanced age or severe comorbid conditions (such as end-stage renal disease). Patients with indications for an ICD and indications for a conventional pacemaker (chronotropic incompetence, the sick sinus syndrome, or atrioventricular conduction abnormalities) should be considered for a dual-chamber ICD rather than a single-chamber ICD. COMPANION ⫽ Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure Trial; CRT ⫽ cardiac resynchronization therapy; ICD ⫽ implantable cardioverter defibrillator; NYHA ⫽ New York Heart Association; RCT ⫽ randomized, controlled trial. † Unless otherwise indicated, values are relative risks. www.annals.org 21 August 2007 Annals of Internal Medicine Volume 147 • Number 4 257 Review Implantable Cardioverter Defibrillators for Left Ventricular Systolic Dysfunction vational studies, we report unadjusted outcomes, and this may introduce bias if there were baseline imbalances between study groups. However, adjustment for study-level variables, such as the incidence of diabetes, may also introduce bias if these variables are not consistently reported and if the spectrum of disease is not clear. Alternatively, using within-study adjusted numbers will lead to bias between studies. Finally, there is a paucity of long-term data (that is, beyond the first 28 months after implantation) in the literature. The importance of long-term data are highlighted by a recent report of 990 patients from a single center followed for up to 10 years, which reported rates of ICD lead failure as high as 20% at 10 years (131). In conclusion, ICDs are efficacious and effective in adults with LV systolic dysfunction. Our systematic review identifies the areas of certainty and uncertainty in the literature about which patients should be considered for an ICD (Table 2). In addition, our findings highlight 3 research priorities. First, the importance of the prospective ACC-NCDR registry for providing “real world” estimates of benefits and risks with these devices cannot be underestimated. For example, recent studies (81) demonstrate that ICDs are being implanted by less experienced providers working in hospitals with lower implantation volumes than in the RCTs of ICDs included in this systematic review, and their effectiveness should be assessed. This would also permit policymakers to track changes in complication rates as device implanters, the tools for implantation, and the sophistication of the devices change over time, and to track effectiveness and complication rates with single-chamber versus dual-chamber ICDs. Second, although more complex ICDs (dual-chamber ICDs, or those capable of antitachycardia pacing) are gaining popularity, evidence comparing such devices with single-lead ICDs, especially in patients without conventional indications for dual-chamber pacing, is limited. Finally, and most important, our meta-analysis reports average treatment effects; the development of risk stratification tools to identify who should (and should not) get an ICD is clearly a research priority. In the words of one editorialist, “it is the entry criterion and not the group actually studied that has driven practice guidelines” (132), and most patients currently implanted with an ICD never receive a therapeutic discharge but are exposed to the risks of ICDs outlined in our report. Thus, we call for the investigators of RCTs on ICDs to collate their individual-patient data to collaboratively explore subgroup effects and define which patients are most likely to benefit from this therapy. From the University of Alberta Evidence-based Practice Center, Edmonton, Alberta, Canada. Disclaimer: The authors of this report are responsible for its content. Statements in the report should not be construed as endorsement by the AHRQ or the U.S. Department of Health and Human Services. Acknowledgments: The authors thank the members of the technical 258 21 August 2007 Annals of Internal Medicine Volume 147 • Number 4 expert panel for this AHRQ report: Dr. Gillian Sanders (Duke University, Durham, North Carolina), Dr. Mark Hlatky (Stanford University, Stanford, California), Dr. Richard Page (University of Washington School of Medicine, Seattle, Washington), Dr. William Abraham (Ohio State University, Columbus, Ohio), and Mary Nix (AHRQ, Rockville, Maryland), who provided direction for the scope and content of the review. They also thank the librarians (Carol Friesen and Tamara Durec) and the external reviewers who submitted written comments on earlier drafts of this report: Dr. David Atkins (AHRQ), Dr. Eric Fain (St. Jude Medical, St. Paul, Minnesota), Dr. Martin Fromer (Centre Hospitalier Universtaire Vaudois, Lausanne, Switzerland), Dr. Gordon Moe (University of Toronto, Toronto, Ontario, Canada), Dr. Robert Rea (Mayo Clinic College of Medicine, Rochester, Minnesota), Dr. John Spertus (University of Missouri–Kansas, Kansas City, Missouri), Bob Thompson (Medtronic, Minneapolis, Minnesota), and Dr. Clyde Yancy (Baylor Heart and Vascular Institute, Dallas, Texas). Grant Support: This manuscript is based on an evidence report pro- duced by the University of Alberta Evidence-based Practice Center under contract 290-02-0023 from the AHRQ, U.S. Department of Health and Human Services. Dr. Ezekowitz is supported by the Canadian Institutes of Health Research Randomized Controlled Trials Program. Dr. Rowe is supported by the 21st Century Canada Research Chairs program through the Government of Canada. Dr. McAlister is a Population Health Scholar supported by the Alberta Heritage Foundation for Medical Research, is a New Investigator of the Canadian Institutes of Health Research, and holds the Merck Frosst/Aventis Chair in Patient Health Management at the University of Alberta, Edmonton. Drs. Ezekowitz, Rowe, and McAlister are also supported by the Faculty of Medicine and Dentistry, University of Alberta, Edmonton, and the Capital Health Authority, Edmonton. Potential Financial Conflicts of Interest: None disclosed. Requests for Single Reprints: Finlay A. McAlister, MD, MSc, Univer- sity of Alberta Hospital, 2E3.24 WMC, 8440 112th Street, Edmonton, Alberta T6G 2R7, Canada; e-mail, [email protected]. Current author addresses are available at www.annals.org. References 1. American Heart Association Statistics Committee and Stroke Statistics Subcommittee. 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Boriani G, Wollmann C, Biffi M, Kühl M, Schuchert A, Sperzel J, et al. Evaluation of a dual chamber implantable cardioverter defibrillator for the treatment of atrial and ventricular arrhythmias. Pacing Clin Electrophysiol. 2003;26: 461-5. [PMID: 12687868] 93. Brockes C, Rahn-Schönbeck M, Duru F, Candinas R, Seifert B, Turina M. ICD implantation with and without combined myocardial revascularisation— incidence of ICD therapy and late survival. Thorac Cardiovasc Surg. 2002;50: 333-6. [PMID: 12457308] 94. Gradaus R, Block M, Brachmann J, Breithardt G, Huber HG, Jung W, et al.; German EURID Registry. Mortality, morbidity, and complications in 3344 patients with implantable cardioverter defibrillators: results fron the German ICD Registry EURID. Pacing Clin Electrophysiol. 2003;26:1511-8. [PMID: 12914630] 95. Hlatky MA, Saynina O, McDonald KM, Garber AM, McClellan MB. Utilization and outcomes of the implantable cardioverter defibrillator, 1987 to 1995. Am Heart J. 2002;144:397-403. [PMID: 12228775] 96. Nademanee K, Veerakul G, Mower M, Likittanasombat K, Krittayapong R, Bhuripanyo K, et al. Defibrillator Versus beta-Blockers for Unexplained Death in Thailand (DEBUT): a randomized clinical trial. Circulation. 2003;107: 2221-6. [PMID: 12695290] 97. Reynolds MR, Cohen DJ, Kugelmass AD, Brown PP, Becker ER, Culler SD, et al. The frequency and incremental cost of major complications among medicare beneficiaries receiving implantable cardioverter-defibrillators. J Am Coll Cardiol. 2006;47:2493-7. [PMID: 16781379] 98. Rosenqvist M, Beyer T, Block M, den Dulk K, Minten J, Lindemans F. Adverse events with transvenous implantable cardioverter-defibrillators: a prowww.annals.org Review spective multicenter study. European 7219 Jewel ICD investigators. Circulation. 1998;98:663-70. [PMID: 9715859] 99. Schläpfer J, Rapp F, Kappenberger L, Fromer M. Electrophysiologically guided amiodarone therapy versus the implantable cardioverter-defibrillator for sustained ventricular tachyarrhythmias after myocardial infarction: results of longterm follow-up. J Am Coll Cardiol. 2002;39:1813-9. [PMID: 12039497] 100. Vollmann D, Ahern T, Gerritse B, Canby RC, Zenker D, Binner L, et al.; Worldwide Medtronic Model 6944 Investigators. Worldwide evaluation of a defibrillation lead with a small geometric electrode surface for high-impedance pacing. Am Heart J. 2003;146:1066-70. [PMID: 14661000] 101. Wiegand UK, LeJeune D, Boguschewski F, Bonnemeier H, Eberhardt F, Schunkert H, et al. Pocket hematoma after pacemaker or implantable cardioverter defibrillator surgery: influence of patient morbidity, operation strategy, and perioperative antiplatelet/anticoagulation therapy. Chest. 2004;126:1177-86. [PMID: 15486380] 102. Stevenson LW. Implantable cardioverter-defibrillators for primary prevention of sudden death in heart failure: are there enough bangs for the bucks? [Editorial] Circulation. 2006;114:101-3. [PMID: 16831996] 103. Poole JE, Johnson GW, Hellkamp AS, Anderson J, Callans DJ, Raitt MH et al. Mortality after appropriate and inappropriate shocks in ScD-HeFT [Abstract]. Heart Rhythm. 2006;3:S40. 104. Multicenter Automatic Defibrillator Implantation Trial II. Health-related quality of life consequences of implantable cardioverter defibrillators: results from MADIT II. Med Care. 2007;45:377-85. [PMID: 17446823] 105. Irvine J, Dorian P, Baker B, O’Brien BJ, Roberts R, Gent M, et al. Quality of life in the Canadian Implantable Defibrillator Study (CIDS). Am Heart J. 2002;144:282-9. [PMID: 12177646] 106. Sears SF Jr, Todaro JF, Lewis TS, Sotile W, Conti JB. Examining the psychosocial impact of implantable cardioverter defibrillators: a literature review. Clin Cardiol. 1999;22:481-9. [PMID: 10410293] 107. 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Should everyone with an ejection fraction less than or equal to 30% receive an implantable cardioverter-defibrillator? Everyone with an ejection fraction ⬍ or ⫽ 30% should receive an implantable cardioverter-defibrillator. Circulation. 2005;111:2537-49; discussion 2537-49. [PMID: 15900623] 112. Buxton AE. Should everyone with an ejection fraction less than or equal to 30% receive an implantable cardioverter-defibrillator? Not everyone with an ejection fraction ⬍ or ⫽ 30% should receive an implantable cardioverter-defibrillator. Circulation. 2005;111:2537-49; discussion 2537-49. [PMID: 15897357] 113. Huikuri HV, Castellanos A, Myerburg RJ. Sudden death due to cardiac arrhythmias. N Engl J Med. 2001;345:1473-82. [PMID: 11794197] 114. Hammill S, Phurrough S, Brindis R. The National ICD Registry: now and into the future. Heart Rhythm. 2006;3:470-3. [PMID: 16567298] 115. MADIT-II Investigators. Time dependence of defibrillator benefit after coronary revascularization in the Multicenter Automatic Defibrillator Implantation Trial (MADIT)-II. J Am Coll Cardiol. 2006;47:1811-7. [PMID: 16682305] 116. European Heart Rhythm Association. ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: a report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death). J Am Coll Cardiol. 2006;48:e247-346. [PMID: 16949478] 117. Multicenter Automatic Defibrillator Implantation Trial (MADIT) II Investigators. Causes and consequences of heart failure after prophylactic implantation of a defibrillator in the multicenter automatic defibrillator implantation 21 August 2007 Annals of Internal Medicine Volume 147 • Number 4 261 Review Implantable Cardioverter Defibrillators for Left Ventricular Systolic Dysfunction trial II. Circulation. 2006;113:2810-7. [PMID: 16769917] 118. Kühlkamp V, Dörnberger V, Mewis C, Suchalla R, Bosch RF, Seipel L. Clinical experience with the new detection algorithms for atrial fibrillation of a defibrillator with dual chamber sensing and pacing. J Cardiovasc Electrophysiol. 1999;10:905-15. [PMID: 10413370] 119. Saad EB, Marrouche NF, Martin DO, Cole CR, Dresing TJ, PerezLugones A, et al. Frequency and associations of symptomatic deterioration after dual-chamber defibrillator implantation in patients with ischemic or idiopathic dilated cardiomyopathy. Am J Cardiol. 2002;90:79-82. [PMID: 12088790] 120. Deisenhofer I, Kolb C, Ndrepepa G, Schreieck J, Karch M, Schmieder S, et al. Do current dual chamber cardioverter defibrillators have advantages over conventional single chamber cardioverter defibrillators in reducing inappropriate therapies? A randomized, prospective study. J Cardiovasc Electrophysiol. 2001; 12:134-42. [PMID: 11232608] 121. Dual Chamber and VVI Implantable Defibrillator Trial Investigators. Dual-chamber pacing or ventricular backup pacing in patients with an implantable defibrillator: the Dual Chamber and VVI Implantable Defibrillator (DAVID) Trial. JAMA. 2002;288:3115-23. [PMID: 12495391] 122. Berenbom LD, Weiford BC, Vacek JL, Emert MP, Hall WJ, Andrews ML, et al. Differences in outcomes between patients treated with single- versus dual-chamber implantable cardioverter defibrillators: a substudy of the Multicenter Automatic Defibrillator Implantation Trial II. Ann Noninvasive Electrocardiol. 2005;10:429-35. [PMID: 16255753] 123. Hughes S. DATAS restores confidence in dual-chamber ICDs. 21 July 2006. theheart.org. [HeartWire ⬎ News] [database on the Internet]. Montreal, Quebec: WebMD; c1999-2006 [cited 26 September 2006]. Accessed at www .theheart.org/article/725387.do on 11 January 2007. 124. American College of Cardiology/American Heart Association Task Force on Practice Guidelines/North American Society for Pacing and Electrophysiology Committee to Update the 1998 Pacemaker Guidelines. ACC/AHA/ NASPE 2002 guideline update for implantation of cardiac pacemakers and antiarrhythmia devices: summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/NASPE Committee to Update the 1998 Pacemaker Guidelines). Circulation. 2002;106:2145-61. [PMID: 12379588] 125. Maisel WH, Sweeney MO, Stevenson WG, Ellison KE, Epstein LM. Recalls and safety alerts involving pacemakers and implantable cardioverter-defibrillator generators. JAMA. 2001;286:793-9. 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Challenges in systematic reviews of therapeutic devices and procedures. Ann Intern Med. 2005;142:1100-11. [PMID: 15968035] 131. Kleemann T, Becker T, Doenges K, Vater M, Senges J, Schneider S, et al. Annual rate of transvenous defibrillation lead defects in implantable cardioverterdefibrillators over a period of ⬎10 years. Circulation. 2007;115:2474-80. [PMID: 17470696] 132. Myerburg RJ, Castellanos A. Clinical research designs and implantable defibrillator indications: spend in the beginning or pay at the end [Editorial]. J Am Coll Cardiol. 2006;47:108-11. [PMID: 16386672] DOWNLOAD IMPORTANT REFERENCES TO CITATION MANAGERS At www.annals.org, article citations may be directly downloaded to any of the following formats: EndNote, Reference Manager, ProCite, BibTeX, or Medlar. 262 21 August 2007 Annals of Internal Medicine Volume 147 • Number 4 www.annals.org Current Author Addresses: Dr. Ezekowitz: 2C2 Cardiology WMC, University of Alberta Hospital, 8440 112th Street, Edmonton, Alberta T6G 2B7, Canada. Dr. Rowe: Department of Emergency Medicine, University of Alberta Hospital, 1G1.42, 8440 112th Street, Edmonton, Alberta T6G 2B7, Canada. Dr. Dryden, Ms. Hooton, Mr. Vandermeer, and Ms. Spooner: University of Alberta Evidence Based Practice Center, Aberhart Centre, 11402 University Avenue, Edmonton, Alberta, T6G 2J3, Canada. Dr. McAlister: University of Alberta Hospital, 2E3.24 WMC, 8440 112th Street, Edmonton, Alberta T6G 2R7, Canada. Appendix Table 1. Description of Randomized Trials Included in the Review* Author, Trial Name, Year (Reference) Primary prevention Moss et al., MADIT, 1996 (14) Design, Duration Patients Randomly Assigned, n Men, n (%) Mean Age (SD), y 95 101 446 87 (92) 93 (92) 386 (86.5) 62 (9) 64 (9) 64 (9) 27 (7) 25 (7) 27 (6) 34 29 100 Mean LVEF (SD) Ischemic Heart Disease, % NYHA Class, % II III II or III ⫽ 63 II or III ⫽ 67 II or III ⫽ 71 IV Bigger, CABG Patch, 1997 (15) RCT, 32 mo ICD OPT CABG ⫹ ICD Moss et al., MADIT II, 2002 (16) RCT, 20 mo CABG ICD 454 742 373 (82.2) 623 (84) 63 (9) 64 (10) 27 (6) 23 (5) 100 100 35 25 Bänsch et al., CAT, 2002 (17) RCT, 66 mo Strickberger et al., AMIOVIRT, 2003 (18) RCT, 2 y OPT All ICD OPT All 490 104 50 54 103 417 (85) 83 (79.8) 43 (86) 40 (74) 72 (69.9) 65 (10) 52 (11) 52 (12) 52 (10) 59 (11) 23 (6) 24 (7) 24 (6) 25 (8) 22 (9) 100 0 0 0 0 34 65.3 66.7 64.1 64 23 34.6 33.3 35.8 19.4 RCT, 15 mo ICD Amiodarone CRT ⫹ OPT 51 52 617 34 (67) 38 (74) 413 (67) 58 (11) 60 (12) Median, 67 22 (10) 23 (8) Median, 20 64 63 Excluded 16 24 87 595 399 (67) Median, 66 Median, 22 55 Excluded 86 14 RCT, 29 mo CRT ⫹ ICD ⫹ OPT OPT only All 308 458 213 (69) 326 (71.2) Median, 68 58 (range, 20–84) Median, 22 21.4 (range, 7–35) 59 0 Excluded 57.4 82 21 18 0 ICD OPT 229 229 166 (72.5) 160 (69.9) 58 (range, 20–84) 58 (range, 22–79) 0 0 54.2 60.7 20.5 21.4 0 0 ICD 332 252 (75.9) 61.5 (10.9) 20.9 (range, 7–35) 21.8 (range, 10–35) 28 (5) 100 NR NR 0 OPT ICD 342 829 262 (76.6) 639 (76) 28 (5) Median, 25 100 52 NR 71 NR 29 0 0 Amiodarone 845 639 (77) Median, 25 50 70 30 0 Placebo 847 655 (77) 62.1 (10.6) Median, 60 (IQR, 52–69) Median, 60 (IQR, 52–68) Median, 59.7 (IQR, 51–68) Median, 25 53 68 32 0 ICD Antiarrhythmic ICD 505 509 328 395 (78) 412 (81) 280 (85.4) 65 (11) 65 (10) 63.3 (9.2) 32 (13) 31 (13) NR 81 81 82.2 I or II ⫽ 48 I or II ⫽ 48 I or II ⫽ 37.8 Amiodarone 331 277 (83.7) 63.8 (9.9) NR 82.9 I or II ⫽ 39.9 ICD Metoprolol Amiodarone 99 97 92 78 (79) 152 (80) 58 (11) 57.5 (10) 46 (19) 46 (17) 73 73.5 59 56 7 0 12 0 III or IV ⫽ 11.0 III or IV ⫽ 10.6 18 0 16 0 Bristow et al., COMPANION, 2004 (19) Kadish et al., DEFINITE, 2004 (20) RCT, 27 mo Study Group Hohnloser et al., DINAMIT, 2004 (21) RCT, 30 mo Bardy et al., SCD-HeFT, 2005 (22) RCT, 46 mo (median) Secondary prevention AVID, 1997 (23) RCT, 18 mo Connolly et al., CIDS, 2000 (24) RCT, 35 mo Kuck et al., CASH, 2000 (25) RCT, 57 mo 0 0 54 0 0 NR II or III ⫽ 74 NR 5 4 0 0 0 0 0 0 13 * AMIOVIRT ⫽ Amiodarone vs. Implantable Defibrillator Randomized Trial; AVID ⫽ Antiarrhythmics Versus Defibrillators; CABG ⫽ coronary artery bypass graft; CABG Patch ⫽ Coronary Artery Bypass Graft Patch Trial; CASH ⫽ Cardiac Arrest Study Hamburg; CAT ⫽ Cardiomyopathy Trial; CIDS ⫽ Canadian Implantable Defibrillator Study; COMPANION ⫽ Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure Trial; CRT ⫽ cardiac resynchronization therapy; DEFINITE ⫽ Defibrillators in Non-Ischemic Cardiomyopathy Treatment Evaluation; DINAMIT ⫽ Defibrillator in Acute Myocardial Infarction Trial; ICD ⫽ implantable cardioverter defibrillator; IQR ⫽ interquartile range; LVEF ⫽ left ventricular ejection fraction; MADIT ⫽ Multicenter Automatic Defibrillator Implantation Trial; NR ⫽ not reported; NYHA ⫽ New York Heart Association; OPT ⫽ optimal pharmacologic therapy; RCT ⫽ randomized, controlled trial; SCD-HeFT ⫽ Sudden Cardiac Death in Heart Failure Trial. W-48 21 August 2007 Annals of Internal Medicine Volume 147 • Number 4 www.annals.org Appendix Table 2. Baseline Characteristics of Patients in Studies Included in the Review* Duration, mo Author, Trial Name, Year (Reference) Design Alter et al., 2005 (26) AVID, 1997 (23) Prospective cohort RCT 46 18 Backenköhler et al., 2005 (27) Prospective cohort 48 Bänsch et al., CAT, 2002 (17) RCT 66 Bardy et al., SCD-HeFT, 2005 (22) RCT 46 Bigger, CABG Patch, 1997 (15) RCT 32 Blangy et al., 2003 (28) Bode-Schnurbus et al., 2003 (29) Bokhari et al., CIDS, 2004 (30) Retrospective cohort Prospective cohort Prospective cohort Bristow et al., COMPANION, 2004 (19) RCT 15 Bruch et al., 2006 (31) Brunckhorst, 2004 (32) Buxton et al., MUSTT, 1999 (33) Prospective cohort Prospective cohort RCT 12 12 39 Capoferri et al., 2004 (34) Prospective cohort 20 Carlsson et al., 2003 (79) Chan and Hayward, 2005 (35) RCT Prospective cohort NR 60 Chan et al., 2006 (36) Connolly et al., CIDS, 2000 (24) Prospective cohort RCT 27 35 Cuesta et al., 2003 (37) Dorian et al., ASTRID, 2004 (38) Dorian et al., SHIELD, 2004 (80) Dubner et al., 2005 (39) Duray et al., 2005 (40) Elhendy et al., 2005 (41) Ellenbogen et al., 2003 (42) Ermis et al., 2003 (43) Prospective cohort RCT RCT Retrospective cohort Retrospective cohort Prospective cohort Prospective cohort Retrospective cohort 30 12 12 27 26 34 69 15 Ermis et al., 2004 (77) Evonich et al., 2004 (44) Friedman et al., 2006 (81) Prospective cohort Retrospective cohort RCT 57 72 6 Gaita et al., 2000 (45) Gatzoulis et al., 2005 (46) Prospective cohort Prospective cohort 12 33 Greenberg et al., 2002 (47) Grimm et al., 2002 (48) Grimm et al., 2006 (82) Ho et al., 2005 (49) Hohnloser et al., DINAMIT, 2004 (21) Retrospective cohort Prospective cohort Retrospective cohort Retrospective cohort RCT 31 35 38 53 30 Hreybe et al., 2006 (83) Kadish et al., DEFINITE, 2004 (20) Prospective cohort RCT 48 29 Koplan et al., 2006 (50) Kuck et al., CASH, 2000 (25) Retrospective cohort RCT 40 57 Lampert et al., 2004 (51) Leosdottir et al., 2006 (52) Lickfett et al., 2004 (84) Moss et al., MADIT, 1996 (14) Retrospective cohort Retrospective cohort Retrospective cohort RCT 30 120 47 27 Moss et al., MADIT II, 2002 (16) RCT 25 24 132 20 Study Group Sample Size, n Men, n (%) Mean Age (SD), y Ischemic Heart Disease, % ICD ICD Antiarrhythmic All participants Secondary prevention Primary prevention All participants ICD Control ICD Amiodarone CABG ⫹ ICD CABG Participants with LVEF ⱕ0.35 All participants ICD Amiodarone CRT ⫹ OPT CRT ⫹ ICD ⫹ OPT OPT only All participants All participants EP–Antiarrhythmics No antiarrhythmics Secondary prevention Primary prevention All participants All participants ICD Control ICD ICD Amiodarone All participants All participants Placebo group All participants All participants ICD ICD All participants ICD No ICD All participants All participants ICD (dual-chamber) ICD (ventricular only) All participants All participants Primary prevention Secondary prevention All participants All participants All participants ICD ICD Control All participants All participants ICD Control All participants ICD Antiarrhythmics All participants All participants All participants ICD Control ICD Conventional treatment 440 1885 357 (81.1) 395 (78) 412 (81) 196 (80) 157 (78) 39 (91) 83 (79.8) 43 (86) 40 (74.1) 639 (77) 639 (76) 386 (86.5) 373 (82.2) 124 (86.1) 132 (80) 50 (83) 50 (83) 413 (67) 399 (67) 213 (69) 67 (80) 97 (93.3) 316 (90) 318 (90) NR NR NR 86 (90) NR NR 339 (86) 280 (85.4) 277 (83.7) 115 (95.8) 124 (83.2) 199 (93) 578 (75) 309 (82) 63 (70) 58 (78.4) 231 (74.5) 40 (67.8) 191 (76.1) 96 (76.1) 122 (79.7) 163 (81) 156 (78) 88 (92) 142 (84) 18 (100) 124 (82.1) 630 (86) 82 (81) 83 (89) 288 (80) 252 (75.9) 262 (76.6) 181 (79) 326 (71.2) 166 (72.5) 160 (69.9) 285 (82) 78 (79) 152 (80) 340 (85) 44 (71) 87 (83) 87 (92) 93 (92) 623 (84) 417 (85) 58 (14) 65 (11) 65 (10) 62.8 (0.8) 63 (11) 62 (10) 52 (11) 52 (12) 52 (10) Median, 60.1 (IQR, 51.9–69.2) Median, 60.4 (IQR, 61.7–68.3) 64 (9) 63 (9) 60.5 (11.9) 61.8 (9.7) 64 (9.2) 64 (8.7) Median, 67 Median, 66 Median, 68 60 (12) 67 (10) Median, 67 (IQR, 60–72) Median, 66 (IQR, 58–72) 55 (13) 49 (15) 53 (13.9) 61 (10.3) 66.2 68.6 66 (9.9) 63.3 (9.2) 63.8 (9.9) 63.3 (9) 60 (13) 62 (12) 60 (13) 63.6 (10) 65 (13) 62 (16) 49.3 (11.9) 51.1 (9.9) 48.9 (12.3) 69 (11.5) 65.6 (12.6) 64.3 (11.3) 65.1 (11.3) 66 (8) 59.9 (12.5) 57 (18) 61 (12) 62.6 (12.4) 51 (14) 56 (13) 62 (13) 61.5 (10.9) 62.1 (10.6) 63 (14) 58.3 (range, 20.3–83.9) 58.4 (range, 20.3–83.9) 58.1 (range, 21.8–78.7) 70 (8) 58 (11) 57.5 (10) 67.4 (SE ⫾1.3) 58 (14) NR 62 (9) 64 (9) 64 (10) 65 (10) 48 81 81 75.1 73.8 81 0 0 0 52 50 100 100 72.9 72.7 80 80 54 55 59 74 100 96 93 70 67 69 67.7 100 100 100 82.2 82.9 66.7 71.1 NR 39.7 84 48.9 65 45.2 44.1 45.4 56 64.4 81 81 NR 60 78 58 79 NR 34.4 68 100 100 75 0 0 0 80.6 73 74 100 62 65 34 29 100 100 245 104 2521 1055 283 603 120 1520 98 104 2202 100 96 6996 395 659 120 149 214 770 375 90 74 310 158 153 400 96 169 732 101 93 360 674 230 458 348 293 650 62 105 196 1232 NYHA Class, % Mean LVEF (SD) II III IV 49 I or II ⫽ 48 I or II ⫽ 48 NR NR NR 65.3 66.7 64.1 57.4 54.2 II or III ⫽ 71 II or III ⫽ 74 NR 0 I or II ⫽ 95 I or II ⫽ 95 Excluded Excluded Excluded 2.7 (0.5) NR 39 38 NR NR NR NR NR NR NR I or II ⫽ 37.8 I or II ⫽ 39.9 NR 51.7 43 I or II ⫽ 81 43.5 NR NR 15.8 13.6 16.3 NR 34 NR NR II, III, or IV ⫽ 100 NR NR NR NR 61 38 NR 95 98 NR 57 54 61 NR 59 59 NR NR NR II or III ⫽ 63 II or III ⫽ 67 35 34 37.3 7 12 NR NR NR 34.6 33.3 35.8 21.0 21.5 0 0 NR 100 III or IV ⫽ III or IV ⫽ 87 86 82 29 (10) NR 24 25 NR NR NR NR NR NR NR III or IV ⫽ III or IV ⫽ III or IV ⫽ 9.5 9 III or IV ⫽ III or IV ⫽ NR NR 58.4 61 57.8 III or IV ⫽ 44 NR NR 22 (6) NR NR NR NR 35 58 NR 40 49 III or IV ⫽ 21 21 21 NR 18 18 NR NR NR 0 0 25 23 2 0 0 NR NR NR 0 0 0 Excluded Excluded 27 (6) 27 (6) NR 0 33.9 (12.5) 32.1 (11.1) 13 14 18 NR NR 0 0 NR NR NR NR NR NR NR 34.3 (14.5) 33.3 (14.1) 33.7 (10.9) 0 Excluded 37.7 (14.3) 32.8 (11.4) NR NR 18.7 25.4 17.1 NR 0 NR NR NR NR NR NR NR 0 4 NR Excluded Excluded 17 Excluded Excluded Excluded NR 0 0 NR NR NR NR NR 5 4 5 5 11 10.6 22.5 19 23.5 87 45 34 (15) 32 (13) 31 (13) 35.6 (15.4) 36 (16) 34 (12) 24 (7) 24 (6) 25 (8) Median, 24.0 (IQR, 19.0–30.0) Median, 25.0 (IQR, 20.0–30.0) NR NR 27 (5) 32.5 (13.6) NR NR Median, 20 Median, 22 Median, 22 NR 35 (15) Median, 30 (IQR, 20–35) Median, 29 (IQR, 22–35) 35 (13) 36 (13) 35.3 (12.9) 34.1 (13.2) NR NR 26.2 (6.0) NR NR NR 35 (15) 34 (14) NR NR 33.7 (11.9) 34 (11) NR 18.7 (6.8) 20.8 (9.8) 22 (8.7) 25.4 (9.01) 32 (13) 32 (13) NR 34.2 (14) 28 (10) 35 (14) 29.2 (11.2) 25 (8) NR 33 (17) 28 (5) 28 (5) 26 (13) 21.4 (range, 7–35) 20.9 (range, 7–35) 21.8 (range, 10–35) 30 (11) 46 (19) 46 (17) 31.6 (SE, ⫾1.7) 40% ⱕ0.40 31 (7) 27 (7) 25 (7) 23 (5) 23 (6) Continued on following page www.annals.org 21 August 2007 Annals of Internal Medicine Volume 147 • Number 4 W-49 Appendix Table 2—Continued Author, Trial Name, Year (Reference) Design Duration, mo Study Group Nazarian et al., 2005 (53) Niehaus et al., 2003 (85) Noseworthy et al., 2004 (54) Pappone et al., 2003 (55) Parkash et al., 2006 (56) Pires et al., 2002 (57) Pires et al., 2006 (58) Raitt et al., 2005 (59) Raviele et al., BEST⫹ICD, 2005 (60) Rienstra et al., 2007 (61) Robin et al., 2006 (62) Russo et al., 2003 (63) Saba et al., 2003 (64) Retrospective cohort Retrospective cohort Retrospective cohort Prospective cohort Retrospective cohort Retrospective cohort Retrospective cohort RCT RCT Prospective cohort Retrospective cohort Prospective cohort Retrospective cohort 36 12 84 28 38 24 22 120 24 31 132 16 48 Saeed et al., LESS, 2003 (86) Sánchez et al., 2005 (65) Prospective cohort Case–control 8 NR Sánchez et al., 2006 (66) Schaer et al., 2006 (67) Sears et al., 2004 (68) Soundarraj et al., 2006 (69) Retrospective cohort Prospective cohort Prospective cohort Retrospective cohort 22 18 14 2 Takahashi et al., 2002 (70) Tandri et al., 2006 (71) Telfer et al., 2002 (72) Theuns et al., 2004 (87) Retrospective cohort Retrospective cohort Retrospective cohort RCT 12 276 26 12 Theuns et al., 2005 (88) Theuns et al., 2005 (73) Tiroke et al., 2003 (89) Trappe, 2002 (74) Prospective cohort Prospective cohort Retrospective cohort Prospective cohort 60 48 60 28 All participants All participants All participants All participants All participants ICD All participants ICD (placebo group) All participants All participants All participants All participants ICD Control All participants ICD Conventional therapy All participants All participants All participants All ICD (single-chamber) ICD (dual-chamber) All participants All participants ICD ICD (single-chamber) ICD (dual-chamber) All participants All participants All participants All participants All participants Wase et al., 2004 (75) Wilkoff et al., EMPIRIC, 2006 (78) Zecchin et al., 2004 (78) Retrospective cohort RCT Retrospective cohort 48 12 24 ICD All participants All participants Non-LVSD (for peri-implantation safety only) Al-Khatib et al., 2005 (90) Bänsch et al., 2004 (91) Boriani et al., 2003 (92) Brockes et al., 2002 (93) Gradaus et al., 2003 (94) Hlatky et al., 2002 (95) Nademanee et al., DEBUT, 2003 (96) Reynolds et al., 2006 (97) Rosenqvist et al., 1998 (98) Schläpfer et al., 2002 (99) Vollmann et al., 2003 (100) Wiegand et al., 2004 (101) Retrospective cohort RCT RCT Retrospective cohort Retrospective cohort Retrospective cohort RCT Retrospective cohort Prospective cohort Prospective cohort RCT Retrospective cohort 33 12 6 72 34 84 36 12 4 63 12 144 ICD ICD ICD ICD ICD ICD ICD ICD ICD ICD ICD ICD Sample Size, n 94 25 637 135 469 2030 861 100 143 290 585 51 35 Men, n (%) Mean Age (SD), y Ischemic Heart Disease, % 55 (11) 60.8 (12) 74.9 (4.4) 64 (11) 65 (15) 64.4 (12.4) 65.4 (12.7) 62 (13) 66.5 (9.6) 59.9 (12.5) 63 (15) 70 (9) (range, 41–98) 51 (12) 51 (12) 64 (12) 60 (16) 61 (13) 66.7 (9.3) 56.4 (12.7) 65 (13) 67 (11) 68 (11) 66 (11) 64 62 (11) 59 (13) 57 (17) 61 (10) 59 (14) 60 (13) 59 (11) 62 (range, 51–72) 57 (11) 45 72 80 43 62 78 57 71 100 72 60 100 20 73 63 47 59 100 0 69 81 83 75 61 72 NR 72 84 78 71 72 77 NR NYHA Class, % II III IV 20 NR I or II ⫽ 90.1 0 ⱕ II ⫽ 81 55 NR 14 NR I or II ⫽ 88 NR NR Excluded Excluded 42 NR NR NR NR NR NR 35 NR NR III or III or III or NR 50 NR 11 NR NR III or III or 23 NR NR NR NR NR NR 33 NR NR 28 (6) 31 NR NR 8 Excluded ⬍1 NR NR 17 26 0 Excluded Excluded NR NR NR NR NR III or IV ⫽ 23 NR NR NR NR NR III or IV ⫽ 28 38 II or III ⫽ 29 III ⫽ 22 NR III or IV ⫽ 14.5 NR NR NR NR NR NR NR NR 0 2 0 25 (10) 35 (14) 34.1 (12.1) NR 35 (16) 33.7 (13.8) 24.1 (10.4) 34 (15) 31.1 (4.1) 29 (7.8) 33 (15) 29 (9) 21.9 (6.8) 22.1 (9.7) 33.6 (14.8) 27 (7) 27 (6) 26.6 (7.7) 25 (8.8) 30.5 (16.4) 26.2 (8.9) 26.4 (9.1) 25.6 (8.3) 33 (15) 33 (11) 22 (7) 29 (11) 31 (10) 30 (10.5) 31 (14) 35 (15) NR NR NR 0 NR 29 (12.5) 32.0 (12.7) 26.5 (7.6) NR 16.6 NR NR 20.9 NR 0 NR 23.1 NR 16.6 NR NR 0 NR NR 1.1 NR 0 NR 0.9 NR 0 NR NR 37.5 (13.5) 46 (16) 36 (12) 70.6% ⬎0.30 NR 66.1 (10.3) NR 39 (17) NR 37.5 (13.5) 46 (16) 127 326 149 410 69 (73) 20 (80) 169 (80) 102 (76) 356 (76) 1654 (81.5) 641 (77) 86 (86) 98 (71) 231 (80) 462 (79) 41 (92) 29 (82.9) 114 (71.7) 38 (79) 15 (79) 26 (81) 93 (89) 50 (86) 73 (83) 297 (77) 226 (77) 71 (78) 144 (81) 1050 (76) 26 (96) 24 (83) 23 (74) 47 (78) 216 (83) 105 (83) 136 (91.3) 368 (89.8) 256 900 54 66 (71) 731 (81.2) 43 (79.6) 66.5 (12.2) 65 (12.6) 52.5 (17.2) NR 69.4 0 NR 38 NR NR NR NR NR I or II ⫽ 72 42 I or II ⫽ 12 II ⫽ 37 NR I or II ⫽ 47 I or II ⫽ 76 9854 102 89 130 3344 22 565 47 30 984 778 41 542 372 7724 (78.4) NR 69 (77.5) 115 (88.5) 2682 (80.2) 18 255 (80.9) 45 (95.7) 24 401 (78.8) 635 (81.6) 7724 (78.4) NR 69 (77.5) NR NR 64.1 (12.5) 61 (11) 61.1 (12.1) 71.5 40.9 (11) NR 58 (13) NR NR 64.1 (12.5) NR 82.4 60 100 64.6 6 NR NR 58 NR 82.4 60 NR 58.8 60 NR 54.3 NR 0 NR 53.3 NR 58.8 60 229 102 123 58 88 386 295 91 178 1382 379 60 Mean LVEF (SD) IV ⫽ 100 IV ⫽ 19 IV ⫽ 19 IV ⫽ 100 IV ⫽ 100 * ASTRID ⫽ Atrial Sensing Trial to prevent Inappropriate Detections; AVID ⫽ Antiarrhythmics Vs. Defibrillators; BEST⫹ICD ⫽ BEta-blocker STrategy plus ICD trial; CABG ⫽ coronary artery bypass grafting; CABG Patch ⫽ Coronary Artery Bypass Graft Patch Trial; CASH ⫽ Cardiac Arrest Study Hamburg; CAT ⫽ Cardiomyopathy Trial; CIDS ⫽ Canadian Implantable Defibrillator Study; COMPANION ⫽ Comparison of Medical Therapy, Pacing, and Defibrillation in Chronic Heart Failure Trial; CRT ⫽ cardiac resynchronization therapy; DEBUT ⫽ Defibrillator versus -blockers for unexplained death in Thailand; DEFINITE ⫽ Defibrillators in Non-Ischemic Cardiomyopathy Treatment Evaluation; DINAMIT ⫽ Defibrillator in Acute Myocardial Infarction Trial; EMPIRIC ⫽ Comparison of Empiric to Physician-Tailored Programming of Implantable Cardioverter Defibrillators; EP ⫽ electrophysiology; ICD ⫽ implanted cardioverter defibrillator; IQR ⫽ interquartile range; LESS ⫽ Low-Energy Safety Study; LVEF ⫽ left ventricular ejection fraction; LVSD ⫽ left ventricular systolic dysfunction; MADIT ⫽ Multicenter Automatic Defibrillator Implantation Trial; MUSTT ⫽ Multicenter Unsustained Tachycardia Trial; NR ⫽ not reported; NYHA ⫽ New York Heart Association; OPT ⫽ optimal pharmacologic therapy; RCT ⫽ randomized, controlled trial; SCD-HeFT ⫽ Sudden Cardiac Death in Heart Failure Trial; SHIELD ⫽ Shock Inhibition Evaluation With Azimilide. W-50 21 August 2007 Annals of Internal Medicine Volume 147 • Number 4 www.annals.org