Systematic Review: Implantable Cardioverter Deﬁbrillators ...library.tasmc.org.il/ in LV... ·...

Systematic Review: Implantable Cardioverter Defibrillators for Adultswith Left Ventricular Systolic DysfunctionJustin 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 dysfunctionhave an increased risk for ventricular arrhythmias.

Purpose: To summarize the evidence about benefits and harms ofimplantable cardioverter defibrillators (ICDs) in adult patients withLV systolic dysfunction.

Data Sources: A search of electronic databases (including MED-LINE, EMBASE, Cochrane Central, and U.S. Food and Drug Admin-istration reports) from 1980 through April 2007, not limited bylanguage of publication, was supplemented by hand searches andcontact with study authors and device manufacturers.

Study Selection: Two reviewers independently selected studies onthe basis of prespecified criteria. They selected 12 randomized,controlled trials (RCTs) (8516 patients) that reported on mortalityand 76 observational studies (96 951 patients) that examined safetyor effectiveness.

Data Extraction: Data were extracted in duplicate and indepen-dently by 2 reviewers.

Data Synthesis: In adult patients with LV systolic dysfunction, 86%of whom had New York Heart Association class II or III symptoms,

ICDs reduced all-cause mortality by 20% (95% CI, 10% to 29%)in the RCTs and by 46% (CI, 32% to 57%) in the observationalstudies. Death associated with implantation of ICDs occurred during1.2% (CI, 0.9% to 1.5%) of procedures. The frequency of post-implantation 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 dis-charges 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 re-ported nonfatal outcomes. Few studies evaluated dual-chamberICDs. Lack of individual-patient data prevents identification ofsubgroup-specific effects.

Conclusions: Implantable cardioverter defibrillators are efficaciousin reducing mortality for adult patients with LV systolic dysfunction,and this benefit extends to nontrial populations. Improved riskstratification tools to identify patients who are most likely to benefitfrom ICD are needed.

Ann Intern Med. 2007;147:251-262. www.annals.orgFor author affiliations, see end of text.

Left ventricular (LV) systolic dysfunction carries a highrisk for sudden cardiac death (1). Implantable cardio-

verter defibrillators (ICDs) can potentially mitigate thisrisk by delivering rapid life-saving therapy and have beensubstantially refined since their initial development in thelate 1970s (2). Randomized, controlled trials (RCTs) havetested the efficacy of ICDs in high-risk individuals. Wepreviously reported a systematic review of 8 RCTs (3RCTs of secondary prevention in survivors of sudden car-diac death; 5 RCTs of primary prevention in patients with-out a history of ventricular arrhythmias) demonstrating a26% reduction in all-cause mortality and a 57% reductionin sudden cardiac death with ICDs (3). Since then, addi-tional RCTs of primary prevention have been published,and questions have arisen about the generalizability of theRCT results for ICDs to clinical practice. In particular, it isuncertain whether the benefits of ICDs seen in the trialsextend to nontrial populations and whether the risks asso-ciated with ICDs may be higher in clinical practice thanreported in trials.

Given the public policy implications, we extended ourprevious systematic review of the efficacy (that is, the risksand benefits of a therapy when tested under ideal circum-stances) (4) of ICDs in patients with LV systolic dysfunc-tion by updating it with recently published RCTs thatexamined efficacy. In addition, we expanded the review toinclude data from observational studies to determine the

effectiveness (that is, the risks and benefits of a therapywhen tested under usual clinical practice conditions) andsafety of ICDs when used in clinical practice.

METHODS

A study protocol meeting Cochrane criteria, includingall of the elements described briefly in the following sec-tions, was developed and followed by the study authors inconjunction with the Agency for Healthcare Research andQuality (AHRQ).

Search StrategyWe sought studies published between 1980 and 27

April 2007 by searching MEDLINE, Ovid MEDLINE In-Process & Other Non-Indexed Citations, Cochrane Cen-tral Register of Controlled Trials, Cochrane Database ofSystematic Reviews, Database of Abstracts of Reviews of

See also:

Web-OnlyAppendix TablesCME quizConversion of figures and tables into slidesAudio summary

Annals of Internal Medicine Review

© 2007 American College of Physicians 251

Effects, Health Technology Assessment Database, EMBASE,Science Citation Index Expanded (via Web of Science),International Pharmaceutical Abstracts, PubMed, NationalLibrary of Medicine Gateway, OCLC ProceedingsFirst andPapersFirst, Computer Retrieval of Information on Scien-tific Projects, various trial registries (including the NationalResearch Register [United Kingdom], Australian ClinicalTrials Registry, ClinicalTrials.gov, and Current ControlledTrials), and U.S. Food and Drug Administration reports.In addition, we hand-searched abstracts from the annualHeart Rhythm Society meetings and the reference lists ofreview articles and included studies; we also contactedauthors of included studies for additional citations andinformation. Unpublished studies and individual-patientdata were sought from device manufacturers, includingMedtronic (Minneapolis, Minnesota), Guidant Corp. (In-dianapolis, Indiana), and St. Jude Medical (St. Paul, Min-nesota). The search was not limited by language or publi-cation status.

The search terms included MedtronicInSync, ELA med-ical, Guidant, St. Jude, implantable defibrillators, implant-able cardioverter defibrillators, AICD, ICD, single chamberICD, dual chamber ICD, congestive heart failure, CHF,chronic heart failure, and heart diseases. A full list of searchstrategies (adapted for each database) and search results areavailable at www.ahrq.gov/clinic/tp/defibtp.htm (5).

Study SelectionWe selected original research studies that had at least

25 participants and reported mortality or peri- or post-

implantation complications with ICDs in adult patientswith LV systolic dysfunction (left ventricular ejection frac-tion [LVEF] �0.35, regardless of whether the patients hadheart failure symptoms). To address efficacy questions, werestricted the analyses to RCTs. To address effectivenessquestions, we expanded our inclusion criteria to includeobservational studies with contemporaneous comparisongroups (such as cohort studies) and RCTs that did notreport efficacy outcomes. To address safety questions, weincluded evidence from both RCTs and observationalstudies (including those without contemporaneous controlgroups, such as case series and registry data).

Data Extraction and AnalysisStudy selection, quality assessment, and data extrac-

tion were completed by several investigators in duplicateand independently, using the methods recommended bythe Quality of Reporting of Meta-analyses (QUOROM)group (6). We assessed quality by using the methods ofSchulz and colleagues (7), the 5-item Jadad scale (8), andthe 27-point Downs and Black scale (9). Publication biaswas assessed visually by using funnel plots and quantita-tively by using the rank correlation test (10), the graphicaltest (11), and the trim-and-fill method (12). Random-effects models were used to calculate pooled relative risks(RRs) in Review Manager 4.2.5 (Cochrane Collaboration,Copenhagen, Denmark). The length of study follow-upversus all-cause mortality was plotted for each study, andinverse variance–weighted least-squares regression was usedto create a best-fit line. Postimplantation complicationswere expressed per 100 patient-years (calculated by multi-plying the frequency of events in each study by the dura-tion of follow-up, and standardizing to a denominator of100) and are unadjusted rates. All results were reportedwith 95% CIs and, where appropriate, SDs or SEs. Statis-tical heterogeneity was quantified by using the I2 statistic(13). In addition to examining for differences in pointestimates across study designs and study quality, we ex-plored device efficacy in different patient subgroups by us-ing meta-regression. Covariates tested included presence ofcardiac resynchronization therapy, length of follow-up,ischemic etiology, New York Heart Association (NYHA)class, age, QRS interval, LVEF, and primary versus second-ary prevention.

Role of the Funding SourceThe 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 tosubmit the manuscript for publication.

RESULTS

Literature SearchFrom 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

Figure 1. Flow diagram of study identification and selection.

RCT � randomized, controlled trial.

Review Implantable Cardioverter Defibrillators for Left Ventricular Systolic Dysfunction

252 21 August 2007 Annals of Internal Medicine Volume 147 • Number 4 www.annals.org

and 48 observational studies [25 retrospective and 23 pro-spective]) for the ICD effectiveness review (27–78), and 64studies (86 809 patients from 11 efficacy RCTs, 10 RCTswithout efficacy outcomes, and 43 observational studies[24 retrospective and 19 prospective]) for the ICD safetyreview (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 listof search strategies, search results, detailed quality assess-ments for each included study, and tests for publicationbias are available at www.ahrq.gov/clinic/tp/defibtp.htm(5). No publication bias was seen on the funnel plots.

RCTs with Efficacy DataThe 12 efficacy RCTs varied in quality (ranging from

1 to 3 on the Jadad scale) and duration (ranging from 15to 66 months). All but 2 trials (16, 19) evaluated single-chamber ICDs (although no trials reported protocol adher-ence to single-chamber vs. dual-chamber ICDs). All pa-tients in the RCTs had LV systolic dysfunction: MeanLVEF ranged from 0.21 to 0.28 in the primary preventiontrials and from 0.32 to 0.46 in the secondary preventiontrials. Most patients also had symptoms of heart failure:

50% had NYHA class II symptoms at baseline; 36%, classIII symptoms; and 3%, class IV symptoms. Eleven percentof trial participants were in NYHA class I at baseline (Ap-pendix Table 1, available at www.annals.org). The meanage of RCT participants was 61 years (SD, 4), 74% weremale, and 59% had ischemic heart disease.

Use of ICDs reduced all-cause mortality in patientswith LV systolic dysfunction by 20% (95% CI, 10% to29%; I2 � 44.4%) (Figure 2), largely because of a 54%relative reduction (CI, 37% to 63%; I2 � 0%) in suddencardiac deaths. In patients with LV systolic dysfunction,ICDs were equally beneficial in reducing all-cause mortal-ity in both primary prevention trials (RR, 0.81 [CI, 0.69 to0.95]; I2 � 53.1% across 9 RCTs) and secondary preven-tion trials (RR, 0.77 [CI, 0.65 to 0.91]; I2 � 13.2% across3 RCTs) (P for this indirect comparison � 0.56).

A single trial included cardiac resynchronization ther-apy in both study groups for its comparison of ICDs versuscontrol (19). All-cause mortality (RR, 0.83 [CI, 0.66 to1.05]) was similar to that reported from the remainder ofthe 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 � CoronaryArtery Bypass Graft Patch Trial; CASH � Cardiac Arrest Study Hamburg; CAT � Cardiomyopathy Trial; CIDS � Canadian Implantable DefibrillatorStudy; COMPANION � Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure Trial; DEFINITE � Defibrillators in Non-Ischemic Cardiomyopathy Treatment Evaluation; DINAMIT � Defibrillator in Acute Myocardial Infarction Trial; MADIT � Multicenter AutomaticDefibrillator Implantation Trial; RR � relative risk; SCD-HeFT � Sudden Cardiac Death in Heart Failure Trial.

ReviewImplantable Cardioverter Defibrillators for Left Ventricular Systolic Dysfunction

www.annals.org 21 August 2007 Annals of Internal Medicine Volume 147 • Number 4 253

tion therapy in either study group (RR, 0.79 [CI, 0.69 to0.91]) (P for indirect comparison � 0.92).

Only 1 trial reported a statistically significant differ-ence in the effect of ICDs across NYHA classes: The mor-tality benefits were greater in patients with NYHA class IIsymptoms than in those with NYHA class III symptoms inthe 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 sensitivityanalyses, none of the covariates we examined (duration offollow-up, primary vs. secondary prevention, ischemiccause, presence of cardiac resynchronization therapy,NYHA class, mean age, mean LVEF, or mean QRS dura-tion) contributed to the moderate statistical heterogeneityobserved in our meta-analysis of all-cause mortality. In ad-dition, our estimate of treatment effect was not associatedwith study quality.

Implantable cardioverter defibrillators did not seem tobe associated with an increase in symptoms of heart failureor deteriorations in functional status or quality of life inRCT participants; however, these outcomes were infre-quently reported (see full AHRQ report for details [5]).For example, hospitalizations for heart failure were re-ported in only 2 trials (pooled RR, 1.1 [CI, 0.76 to 1.59]).

Observational Studies and Trials with Effectiveness DataThe 47 cohort studies, 5 nonefficacy RCTs, and 1

case–control study varied in quality (ranging from 7 to 28on the Downs and Black scale) and duration (median, 29months [interquartile range, 19 to 37 months]). All studiesenrolled similar patient populations. Twenty of the 53

studies reported the type of ICD implanted: 18 studiesincluded patients receiving both single- and dual-chamberICDs, 1 study included those receiving dual-chamberICDs only, and 1 study included those receiving single-chamber ICDs only. Fifteen of these studies evaluatedICDs for primary prevention, 4 reported ICD data forsecondary prevention, 30 reported on a mix of primary andsecondary prevention patients, and 4 studies were unclear.All patients in these studies (Appendix Table 2, available atwww.annals.org) had LV systolic dysfunction (mean LVEFranged from 0.19 to 0.46), and most had symptoms ofheart failure (32% were in NYHA class II, 40% were inclass III, and 5% were in class IV). Demographic charac-teristics were similar to those of participants in the RCTsof ICD efficacy: The mean age was 63 years (SD, 13), 82%of patients were male, and 67% had underlying ischemicheart disease.

The pooled effectiveness estimate from the controlledobservational studies suggested a greater benefit from ICDson all-cause mortality (RR, 0.54 [CI, 0.43 to 0.68]) thanhad been seen in the RCTs (Figure 3), but with greaterheterogeneity between studies (I2 � 60.4%). The observa-tional studies demonstrated a reduced frequency of non-cardiac death in ICD recipients (RR, 0.74 [CI, 0.65 to0.85] in 8 studies with 8759 patients; I2 � 0%). We eval-uated the effect of quality (via meta-regression) on all-causemortality. Contrary to expectations, higher-quality studiesreported a greater benefit from ICDs, but this finding wasnot significant (P � 0.09). As shown in Figure 4, mortalityover time was similar in ICD recipients enrolled in RCTs

Figure 3. Effect of implantable cardioverter defibrillators (ICDs) on all-cause mortality in observational studies withcontemporaneous control groups.

MUSTT � Multicenter Unsustained Tachycardia Trial; RR � relative risk.



and in observational studies (both prospective and retro-spective).

Observational Studies and Trials with Harms DataIn 53 studies (Appendix Table 2, available at www

.annals.org) enrolling patients with LV systolic dysfunctiononly (median LVEF, 0.31), rate of success of ICD implan-tation was 99% (CI, 98.8% to 99.3%) and peri-implanta-tion deaths occurred in 1.2% (CI, 0.9% to 1.5%) of pro-cedures. These studies varied in quality (ranging from 18to 27 on the Downs and Black scale) and duration (me-dian, 28 months [interquartile range, 19 to 48 months])but enrolled similar patient populations. In 24 studies, pa-tients received either a dual- or a single-chamber ICD; in 4studies, patients received dual-chamber ICDs only; and in10 studies, patients received single-chamber ICDs only.The remaining studies did not report the type of device.The frequency of postimplantation complications (per 100patient-years) included 1.4 (CI, 1.2 to 1.6) device malfunc-tions, 1.5 (CI, 1.3 to 1.8) lead problems, and 0.6 (CI, 0.5to 0.8) implant site infection. The rate of inappropriatedischarges per 100 patient-years was 19.1 (CI, 16.5 to22.0) in the RCTs and 4.9 (CI, 4.5 to 5.3) in the obser-vational studies (Table 1).

We also examined peri-implantation deaths and suc-cess rates in 12 studies (68 848 patients) that enrolled allpatients undergoing ICD implantation (that is, not justthose patients with LV systolic dysfunction: 1 study ofprimary prevention, 3 studies of secondary prevention, 7studies of both, and 1 study unclear) (90–101). The pro-portions were similar to those reported in the studies re-stricted to patients with LV systolic dysfunction: The im-plantation 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, effective-ness, and safety of ICDs in adult patients with LV dysfunc-tion. The results confirm that ICDs reduce the relative riskfor death by 20% for adults who have an LVEF of 0.35 orless and predominantly NYHA class II and III symptoms.This effect exists regardless of whether a patient has a his-tory of hemodynamically apparent ventricular arrhythmiasor an ischemic cause. Our review goes beyond previousreviews of this topic in demonstrating that 1) the survivalbenefits of ICDs extend beyond the RCT setting and 2)the implantation success rate and safety of ICDs are similarin clinical practice and RCTs. The fact that the controlledobservational studies demonstrated a reduced frequency ofnoncardiac death in ICD recipients suggests that cliniciansselect healthier patients for ICD insertion, and this proba-bly accounts for the larger apparent benefit from ICDs onall-cause mortality in observational studies than in RCTs.

However, our data on patient and device-related com-plication rates highlight the perhaps underappreciated risks

of ICDs, particularly in light of 3 findings. First, threequarters to two thirds of ICD recipients in the observa-tional studies received no therapeutic ICD discharges, andonly 5% to 12% of trial participants received an appropri-ate shock per year (102). Second, the frequency of inap-propriate shocks was surprisingly high, and at least 1 studyhas demonstrated that inappropriate shocks are associatedwith an increase in risk for death (hazard ratio, 1.97 [CI,1.29 to 3.01] in the Sudden Cardiac Death in Heart Fail-ure Trial) (103). Third, although the studies we reviewedinfrequently report quality-of-life outcomes, some studieshave shown that quality of life declines in many ICD re-cipients (104), especially those who experience frequent ICDfirings (105, 106). Not unexpectedly, patient anxiety and psy-chological distress scores increase substantially after an ICDshock (107) or after publicity about device recalls (108).

Thus, whereas the Multicenter Automatic Defibrilla-tor Implantation Trial II and Sudden Cardiac Death inHeart Failure Trial eligibility criteria are commonly citedas a way to identify patients who might benefit from anICD, the development and validation of risk stratificationtools (such as microvolt T-wave alternans [109] or elevatednatriuretic peptide levels [110]) to identify patients whoare most likely to benefit from an ICD are vitally impor-tant (111, 112). This is particularly true because less thanone quarter of patients with cardiac arrest have an LVEFless than 0.30 before the event (113). Although our meta-regressions did not reveal any patient subgroups who werestatistically more or less likely to benefit from an ICD, weshould emphasize that these analyses were post hoc andunderpowered because of the small number of RCTs. A

Figure 4. Scatter plot of all-cause mortality versus lengthof follow-up for recipients of implantable cardioverterdefibrillators who were enrolled in different types ofstudies.

Circle � prospective cohort study; square � randomized, controlledtrial; triangle � retrospective cohort study. Size of plotting character isproportional to the square root of the sample size of study.



meta-analysis of individual-patient data would be necessaryto more thoroughly examine this issue. Indeed, the estab-lishment of the ICD Registry by the American College ofCardiology National Cardiovascular Data Registry (ACC-NCDR) in conjunction with the Heart Rhythm Society isan important initiative that will permit the collection ofcomprehensive data on ICD implantations and long-termoutcomes. These efforts should help to identify whetherparticular patient subgroups derive more or less benefit andwhether specific devices or particular programming vari-ables are associated with improved outcomes (114).

Regardless, the current evidence base does providesome guidance in the selection of candidates for a primaryprevention ICD. For example, because ICDs were not as-sociated with mortality benefits when implanted at thetime of bypass surgery (15), within 40 days of a myocardialinfarction (21), or within 6 months of coronary revascular-ization (hazard ratio, 1.19; P � 0.76) (115), the recom-mendation in the American College of Cardiology/Ameri-can Heart Association/European Society of Cardiology2006 guidelines (116) to delay ICD implantation afteracute coronary events or coronary revascularization is ap-

propriate. Reports that ICD recipients with a baseline QRSinterval of 120 ms or greater are at increased risk for sub-sequent heart failure (117) highlight a subgroup of ICD-eligible patients (those with NYHA III symptoms,LVEF �0.35, and QRS interval �120 ms) who should beconsidered for a combined cardiac resynchronization thera-py–ICD device per the recommendations of the AmericanHeart Association, American College of Cardiology, andHeart Rhythm Society (116).

Our analysis is limited by a paucity of data on dual-chamber ICDs. While 1 study reported a 47% improve-ment in the odds of detecting supraventricular tachycardiaand 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 withdual-chamber ICDs over single-chamber ICDs. Indeed,the largest RCT to date has suggested that dual-chamberICDs may exacerbate heart failure in patients without anindication for dual-chamber pacing (121). In addition, apost hoc analysis of the Multicenter Automatic Defibrilla-tor Implantation Trial II demonstrated a higher risk fordeath or heart failure hospitalization among patients who

Table 1. Peri- and Postimplantation Risks of Implantation of Cardioverter Defibrillators*

Outcome Type of Study Studies, n Raw Data† Pooled Risk Estimates(95% CI)‡

Peri-implantation complicationsDeath RCT (LVSD) 8 35/2014 1.7 (1.2–2.4)

RCT (non-LVSD) 4 0/725 0.0 (0.0–0.4)Observational (LVSD) 20 24/2888 0.8 (0.5–1.2)Observational (non-LVSD) 6 454/34 231 1.3 (1.2–1.5)Total 38 513/39 858 1.3 (1.2–1.4)

Implantation success rate RCT (LVSD) 10 3657/3716 98.4 (98.0–98.8)RCT (non-LVSD) 4 766/777 98.6 (97.5–99.3)Observational (LVSD) 14 2473/2473 100.0 (99.9–100.0)Observational (non-LVSD) 3 4107/4163 98.7 (98.3–99.0)Total 31 11 003/11 129 98.9 (98.7–99.1)

Mechanical complication RCT 5 88/1740 5.1 (4.1–6.2)Observational studies 13 88/1559 5.6 (4.6–6.9)Total 18 176/3299 5.3 (4.6–6.2)

Postimplantation complicationsMechanical malfunction RCT 3 11/1477 0.7 (0.4–1.3)

Observational 6 33/5478 0.6 (0.4–0.8)Total 9 44/6955 0.6 (0.5–0.8)

Device malfunction RCT 5 91/6429 1.4 (1.1–1.7)Observational 5 57/4436 1.3 (1.0–1.7)Total 10 148/10 865 1.4 (1.2–1.6)

Lead problems RCT 6 38/2303 0.9 (0.6–1.2)Observational 10 123/6354 1.9 (1.6–2.3)Total 16 161/10 527 1.5 (1.3–1.8)

Infections RCT 8 58/1232 1.1 (0.8–1.4)Observational 9 18/7037 0.3 (0.2–0.4)Total 17 76/12 436 0.6 (0.5–0.8)

Inappropriate shocks RCT 2 155/810 19.1 (16.5–22.0)Observational 27 556/11 448 4.9 (4.5–5.3)Total 29 711/12 258 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 ofpatients/patient-years.‡ Risk estimates for peri-implantation complications are expressed as percentages. Risk estimates for postimplantation complications are expressed per 100 patient-years.



received a dual-chamber ICD than among those who re-ceived a single-chamber ICD (122). Because the choice ofsingle- 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 morecomorbid conditions; thus, after multivariable adjustment,the excess risks with dual-chamber ICDs were not statisti-cally significant (hazard ratio for death, 1.27 [CI, 0.76 to2.12]; hazard ratio for heart failure hospitalization, 1.27[CI, 0.87 to 1.86]). An unpublished RCT (the DualChamber and Atrial Tachyarrhythmias Adverse EventsStudy) (123), which used different device settings with alonger atrioventricular delay, reported fewer inappropriateshocks with dual-chamber ICDs than with standard single-lead ICDs. Thus, dual-chamber ICDs must be testedagainst single-chamber ICDs in an appropriately poweredRCT before definitive conclusions can be drawn aboutwhich device to use. In the meantime, although the mostrecent guidelines for ICDs and the prevention of suddencardiac death are silent on the indications for dual-chamberdevices (116), we believe it prudent to restrict the use ofdual-chamber ICDs to patients who require an ICD andhave conventional indications for dual-chamber pacing(such as chronotropic incompetence, the sick sinus syn-drome, or atrioventricular conduction abnormalities) (124).

While we report on patient and device-related compli-cation rates in this review, it should be recognized that it isdifficult to estimate the true incidence of ICD device fail-ure. The observed failure rates are probably underestimatedbecause of the tendency to attribute patient deaths to theunderlying disease process rather than unrecognized devicemalfunction. Indeed, an analysis of U.S. Food and Drug

Administration Enforcement Reports over the past decadedemonstrated marked increases in device recall rates overtime (as devices have become smaller and more compli-cated). Currently, ICD recall rates are as high as 16.4 per100 person-years—54% for hardware malfunctions (elec-trical or circuitry malfunctions, battery or capacitor mal-functions, 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 LVdysfunction has been analyzed several times. Results havevaried (126–129); however, no study has accounted forICD advisories and replacements, which increased totalhealth care costs by as much as $90 million per year (125).Since variability in model estimates is due in part to un-certainty about complication rates, our data shouldstrengthen the assumptions upon which these analyses arebased. Accounting for these new data and observationsshould be a priority for all future analyses of ICD cost.

Our systematic review has a few limitations that de-serve consideration, some of which were identified in pre-vious reviews (130). The conclusions of a systematic revieware limited by available data; we sought to minimize this byan extensive search that included gray literature and U.S.Food and Drug Administration reports. We could not ob-tain individual-patient data to explore the subgroups thatget more or less benefit from an ICD; however, we per-formed meta-regression by using aggregate trial-level data,which did not reveal variation across the variables wetested. Because of incomplete reporting of outcomes in theselected studies, certain device-related issues cannot be ex-plored, such as benefits and safety of dual-chamber versussingle-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 High (many RCTs with homogeneous results) Reduced mortality: 0.77 (0.65–0.91) Definite benefitNYHA class II or III High (many RCTs with homogeneous results) Reduced mortality: 0.81 (0.69–0.95)

No significant effect on hospitalizationsfor heart failure: 1.10 (0.76–1.59)

Definite benefit

NYHA class I Low (post hoc metaregression usingaggregate trial data from 12 RCTs)

No significant association inmeta-regression between proportionof patients with class I symptomsand reduction in mortality(P � 0.13)

Inconclusive

Primary prevention in NYHA class IV Moderate (within-RCT comparison, but notprimary aim of RCT; in addition, studyused post hoc metaregression withaggregate trial data from 12 RCTs)

Mortality hazard ratio, 1.27 (0.68–2.37),in CRT-ICD group vs. CRT-alonegroup among patients with class IVsymptoms in COMPANION, but nosignificant association in meta-regression between proportion ofpatients with class IV symptoms andreduction in mortality(P � 0.62)

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 effectsof 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 conventionalpacemaker (chronotropic incompetence, the sick sinus syndrome, or atrioventricular conduction abnormalities) should be considered for a dual-chamber ICD rather than asingle-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.



vational studies, we report unadjusted outcomes, and thismay introduce bias if there were baseline imbalances be-tween study groups. However, adjustment for study-levelvariables, such as the incidence of diabetes, may also intro-duce bias if these variables are not consistently reportedand if the spectrum of disease is not clear. Alternatively,using within-study adjusted numbers will lead to bias be-tween studies. Finally, there is a paucity of long-term data(that is, beyond the first 28 months after implantation) inthe literature. The importance of long-term data are high-lighted by a recent report of 990 patients from a singlecenter followed for up to 10 years, which reported rates ofICD lead failure as high as 20% at 10 years (131).

In conclusion, ICDs are efficacious and effective inadults with LV systolic dysfunction. Our systematic reviewidentifies the areas of certainty and uncertainty in the lit-erature about which patients should be considered for anICD (Table 2). In addition, our findings highlight 3 re-search priorities. First, the importance of the prospectiveACC-NCDR registry for providing “real world” estimatesof benefits and risks with these devices cannot be under-estimated. For example, recent studies (81) demonstratethat ICDs are being implanted by less experienced provid-ers working in hospitals with lower implantation volumesthan in the RCTs of ICDs included in this systematicreview, and their effectiveness should be assessed. Thiswould also permit policymakers to track changes in com-plication rates as device implanters, the tools for implanta-tion, and the sophistication of the devices change overtime, and to track effectiveness and complication rates withsingle-chamber versus dual-chamber ICDs. Second, al-though more complex ICDs (dual-chamber ICDs, or thosecapable of antitachycardia pacing) are gaining popularity,evidence comparing such devices with single-lead ICDs,especially in patients without conventional indications fordual-chamber pacing, is limited. Finally, and most impor-tant, our meta-analysis reports average treatment effects;the development of risk stratification tools to identify whoshould (and should not) get an ICD is clearly a researchpriority. In the words of one editorialist, “it is the entrycriterion and not the group actually studied that has drivenpractice guidelines” (132), and most patients currently im-planted with an ICD never receive a therapeutic dischargebut are exposed to the risks of ICDs outlined in our report.Thus, we call for the investigators of RCTs on ICDs tocollate their individual-patient data to collaboratively ex-plore subgroup effects and define which patients are mostlikely to benefit from this therapy.

From the University of Alberta Evidence-based Practice Center, Edmon-ton, Alberta, Canada.

Disclaimer: The authors of this report are responsible for its content.Statements in the report should not be construed as endorsement by theAHRQ or the U.S. Department of Health and Human Services.

Acknowledgments: The authors thank the members of the technical

expert panel for this AHRQ report: Dr. Gillian Sanders (Duke Univer-sity, Durham, North Carolina), Dr. Mark Hlatky (Stanford University,Stanford, California), Dr. Richard Page (University of WashingtonSchool of Medicine, Seattle, Washington), Dr. William Abraham (OhioState University, Columbus, Ohio), and Mary Nix (AHRQ, Rockville,Maryland), who provided direction for the scope and content of thereview. They also thank the librarians (Carol Friesen and Tamara Durec)and the external reviewers who submitted written comments on earlierdrafts of this report: Dr. David Atkins (AHRQ), Dr. Eric Fain (St. JudeMedical, St. Paul, Minnesota), Dr. Martin Fromer (Centre HospitalierUniverstaire Vaudois, Lausanne, Switzerland), Dr. Gordon Moe (Uni-versity of Toronto, Toronto, Ontario, Canada), Dr. Robert Rea (MayoClinic College of Medicine, Rochester, Minnesota), Dr. John Spertus(University of Missouri–Kansas, Kansas City, Missouri), Bob Thompson(Medtronic, Minneapolis, Minnesota), and Dr. Clyde Yancy (BaylorHeart 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 undercontract 290-02-0023 from the AHRQ, U.S. Department of Health andHuman Services. Dr. Ezekowitz is supported by the Canadian Institutesof Health Research Randomized Controlled Trials Program. Dr. Rowe issupported by the 21st Century Canada Research Chairs programthrough the Government of Canada. Dr. McAlister is a PopulationHealth Scholar supported by the Alberta Heritage Foundation for Med-ical Research, is a New Investigator of the Canadian Institutes of HealthResearch, and holds the Merck Frosst/Aventis Chair in Patient HealthManagement at the University of Alberta, Edmonton. Drs. Ezekowitz,Rowe, and McAlister are also supported by the Faculty of Medicine andDentistry, University of Alberta, Edmonton, and the Capital HealthAuthority, 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.

References1. American Heart Association Statistics Committee and Stroke Statistics Sub-committee. Heart disease and stroke statistics—2006 update: a report from theAmerican Heart Association Statistics Committee and Stroke Statistics Subcom-mittee. Circulation. 2006;113:e85-151. [PMID: 16407573]2. Mirowski M, Mower MM, Reid PR. The automatic implantable defibrillator.Am Heart J. 1980;100:1089-92. [PMID: 7192485]3. Ezekowitz JA, Armstrong PW, McAlister FA. Implantable cardioverter defi-brillators in primary and secondary prevention: a systematic review of random-ized, controlled trials. Ann Intern Med. 2003;138:445-52. [PMID: 12639076]4. Haynes RD, Sackett DL, Guyatt GH. Clinical Epidemiology: How to DoClinical Practice Research. 3rd ed. Philadelphia: Lippincott Williams & Wilkins;2006.5. McAlister FA, Ezekowitz J, Dryden DM, Hooton N, Vandermeer B, FriesenC, et al. The efficacy, effectiveness, and safety of cardiac resynchronization ther-apy and/or implantable cardiac defibrillator in patients with left ventricular sys-tolic dysfunction. Evidence Report/Technology Assessment no. 129. Prepared bythe University of Alberta Evidence-based Practice Center for the Agency forHealthcare Research and Quality under contract no. 290-02-0023. Accessed atwww.ahrq.gov/clinic/tp/defibtp.htm on 15 May 2007.6. Moher D, Cook DJ, Eastwood S, Olkin I, Rennie D, Stroup DF. Improvingthe quality of reports of meta-analyses of randomised controlled trials: theQUOROM statement. Quality of Reporting of Meta-analyses. Lancet. 1999;354:1896-900. [PMID: 10584742]



7. Schulz KF, Chalmers I, Hayes RJ, Altman DG. Empirical evidence of bias.Dimensions of methodological quality associated with estimates of treatment ef-fects in controlled trials. JAMA. 1995;273:408-12. [PMID: 7823387]8. Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ,et al. Assessing the quality of reports of randomized clinical trials: is blindingnecessary? Control Clin Trials. 1996;17:1-12. [PMID: 8721797]9. Downs SH, Black N. The feasibility of creating a checklist for the assessmentof the methodological quality both of randomised and non-randomised studies ofhealth care interventions. J Epidemiol Community Health. 1998;52:377-84.[PMID: 9764259]10. Begg CB, Mazumdar M. Operating characteristics of a rank correlation testfor publication bias. Biometrics. 1994;50:1088-101. [PMID: 7786990]11. Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysisdetected by a simple, graphical test. BMJ. 1997;315:629-34. [PMID: 9310563]12. Duval S, Tweedie R. A nonparametric “trim and fill” method of accountingfor publication bias in meta-analysis. Journal of the American Statistical Associa-tion. 2000;95:89-98.13. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis.Stat Med. 2002;21:1539-58. [PMID: 12111919]14. Moss AJ, Hall WJ, Cannom DS, Daubert JP, Higgins SL, Klein H, et al.Improved survival with an implanted defibrillator in patients with coronary dis-ease at high risk for ventricular arrhythmia. Multicenter Automatic DefibrillatorImplantation Trial Investigators. N Engl J Med. 1996;335:1933-40. [PMID:8960472]15. Bigger JT Jr. Prophylactic use of implanted cardiac defibrillators in patients athigh risk for ventricular arrhythmias after coronary-artery bypass graft surgery.Coronary Artery Bypass Graft (CABG) Patch Trial Investigators. N Engl J Med.1997;337:1569-75. [PMID: 9371853]16. Moss AJ, Zareba W, Hall WJ, Klein H, Wilber DJ, Cannom DS, et al;Multicenter Automatic Defibrillator Implantation Trial II Investigators. Pro-phylactic implantation of a defibrillator in patients with myocardial infarctionand reduced ejection fraction. N Engl J Med. 2002;346:877-83. [PMID:11907286]17. Bansch D, Antz M, Boczor S, Volkmer M, Tebbenjohanns J, Seidl K, et al.Primary prevention of sudden cardiac death in idiopathic dilated cardiomyopa-thy: the Cardiomyopathy Trial (CAT). Circulation. 2002;105:1453-8. [PMID:11914254]18. Strickberger SA, Hummel JD, Bartlett TG, Frumin HI, Schuger CD, BeauSL, et al.; AMIOVIRT Investigators. Amiodarone versus implantable cardio-verter-defibrillator: randomized trial in patients with nonischemic dilated cardio-myopathy and asymptomatic nonsustained ventricular tachycardia—AMIO-VIRT. J Am Coll Cardiol. 2003;41:1707-12. [PMID: 12767651]19. Bristow MR, Saxon LA, Boehmer J, Krueger S, Kass DA, De Marco T, etal.; Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Fail-ure (COMPANION) Investigators. Cardiac-resynchronization therapy with orwithout an implantable defibrillator in advanced chronic heart failure. N Engl JMed. 2004;350:2140-50. [PMID: 15152059]20. Kadish A, Dyer A, Daubert JP, Quigg R, Estes NA, Anderson KP, et al.;Defibrillators in Non-Ischemic Cardiomyopathy Treatment Evaluation(DEFINITE) Investigators. Prophylactic defibrillator implantation in patientswith nonischemic dilated cardiomyopathy. N Engl J Med. 2004;350:2151-8.[PMID: 15152060]21. Hohnloser SH, Kuck KH, Dorian P, Roberts RS, Hampton JR, Hatala R,et al.; DINAMIT Investigators. Prophylactic use of an implantable cardioverter-defibrillator after acute myocardial infarction. N Engl J Med. 2004;351:2481-8.[PMID: 15590950]22. Bardy GH, Lee KL, Mark DB, Poole JE, Packer DL, Boineau R. et al.;Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) Investigators.Amiodarone or an implantable cardioverter-defibrillator for congestive heart fail-ure. N Engl J Med. 2005;352:225-37. [PMID: 15659722]23. A comparison of antiarrhythmic-drug therapy with implantable defibrillatorsin patients resuscitated from near-fatal ventricular arrhythmias. The Antiarrhyth-mics versus Implantable Defibrillators (AVID) Investigators. N Engl J Med.1997;337:1576-83. [PMID: 9411221]24. Connolly SJ, Gent M, Roberts RS, Dorian P, Roy D, Sheldon RS, et al.Canadian implantable defibrillator study (CIDS): a randomized trial of the im-plantable cardioverter defibrillator against amiodarone. Circulation. 2000;101:1297-302. [PMID: 10725290]25. Kuck KH, Cappato R, Siebels J, Ruppel R. Randomized comparison ofantiarrhythmic drug therapy with implantable defibrillators in patients resusci-

tated from cardiac arrest: the Cardiac Arrest Study Hamburg (CASH). Circula-tion. 2000;102:748-54. [PMID: 10942742]26. Alter P, Waldhans S, Plachta E, Moosdorf R, Grimm W. Complications ofimplantable cardioverter defibrillator therapy in 440 consecutive patients. PacingClin Electrophysiol. 2005;28:926-32. [PMID: 16176531]27. Backenkohler U, Erdogan A, Steen-Mueller MK, Kuhlmann C, Most A,Schaefer C, et al. Long-term incidence of malignant ventricular arrhythmia andshock therapy in patients with primary defibrillator implantation does not differfrom event rates in patients treated for survived cardiac arrest. J Cardiovasc Elec-trophysiol. 2005;16:478-82. [PMID: 15877617]28. Blangy H, Sadoul N, de Chillou C, Dodinot B, Magnin-Poull I, Brembilla-Perrot B, et al. [Characteristics and causes of death in 283 patients with im-planted defibrillators]. Arch Mal Coeur Vaiss. 2003;96:7-14. [PMID: 12613144]29. Bode-Schnurbus L, Bocker D, Block M, Gradaus R, Heinecke A, Breit-hardt G, et al. QRS duration: a simple marker for predicting cardiac mortality inICD patients with heart failure. Heart. 2003;89:1157-62. [PMID: 12975406]30. Bokhari F, Newman D, Greene M, Korley V, Mangat I, Dorian P. Long-term comparison of the implantable cardioverter defibrillator versus amiodarone:eleven-year follow-up of a subset of patients in the Canadian Implantable Defi-brillator Study (CIDS). Circulation. 2004;110:112-6. [PMID: 15238454]31. Bruch C, Gotzmann M, Sindermann J, Breithardt G, Wichter T, BockerD, et al. Prognostic value of a restrictive mitral filling pattern in patients withsystolic heart failure and an implantable cardioverter-defibrillator. Am J Cardiol.2006;97:676-80. [PMID: 16490436]32. Brunckhorst C, Binggeli C, Hellermann JP, Scharf Ch, Holzmeister J,Duru F. [ICD therapy in patients with coronary artery disease—incidence ofadequate interventions]. Ther Umsch. 2004;61:271-8. [PMID: 15139319]33. Buxton AE, Lee KL, Fisher JD, Josephson ME, Prystowsky EN, Hafley G.A randomized study of the prevention of sudden death in patients with coronaryartery disease. Multicenter Unsustained Tachycardia Trial Investigators. N Engl JMed. 1999;341:1882-90. [PMID: 10601507]34. Capoferri M, Schwick N, Tanner H, Fuhrer J, Delacretaz E. Incidence ofarrhythmic events in patients with implantable cardioverter-defibrillator for pri-mary and secondary prevention of sudden cardiac death. Swiss Med Wkly. 2004;134:154-8. [PMID: 15106019]35. Chan PS, Hayward RA. Mortality reduction by implantable cardioverter-defibrillators in high-risk patients with heart failure, ischemic heart disease, andnew-onset ventricular arrhythmia: an effectiveness study. J Am Coll Cardiol.2005;45:1474-81. [PMID: 15862422]36. Chan PS, Chow T, Kereiakes D, Schloss EJ, Waller T, Eagle K, et al.Effectiveness of implantable cardioverter-defibrillators in patients with ischemicheart disease and left ventricular dysfunction. Arch Intern Med. 2006;166:2228-33. [PMID: 17101941]37. Cuesta A, Mont L, Rogel U, Valentino M, Matas M, Brugada J. Compar-ison of effectiveness of implantable cardioverter defibrillator in patients with id-iopathic dilated cardiomyopathy versus those with proved coronary heart disease.Am J Cardiol. 2003;92:1227-30. [PMID: 14609607]38. Dorian P, Philippon F, Thibault B, Kimber S, Sterns L, Greene M, et al.;ASTRID Investigators. Randomized controlled study of detection enhancementsversus rate-only detection to prevent inappropriate therapy in a dual-chamberimplantable cardioverter-defibrillator. Heart Rhythm. 2004;1:540-7. [PMID:15851216]39. Dubner S, Valero E, Pesce R, Zuelgaray JG, Mateos JC, Filho SG, et al. ALatin American registry of implantable cardioverter defibrillators: the ICD-LABOR study. Ann Noninvasive Electrocardiol. 2005;10:420-8. [PMID:16255752]40. Duray G, Richter S, Manegold J, Israel CW, Gronefeld G, Hohnloser SH.Efficacy and safety of ICD therapy in a population of elderly patients treated withoptimal background medication. J Interv Card Electrophysiol. 2005;14:169-73.[PMID: 16421693]41. Elhendy A, Chapman S, Porter TR, Windle J. Association of myocardialischemia with mortality and implantable cardioverter-defibrillator therapy in pa-tients with coronary artery disease at risk of arrhythmic death. J Am Coll Cardiol.2005;46:1721-6. [PMID: 16256875]42. Ellenbogen KA, Wood MA, Shepard RK, Clemo HF, Vaughn T, Hollo-man K, et al. Detection and management of an implantable cardioverter defibril-lator lead failure: incidence and clinical implications. J Am Coll Cardiol. 2003;41:73-80. [PMID: 12570948]43. Ermis C, Zadeii G, Zhu AX, Fabian W, Collins J, Lurie KG, et al. Im-proved survival of cardiac transplantation candidates with implantable cardio-



verter defibrillator therapy: role of beta-blocker or amiodarone treatment. J Car-diovasc Electrophysiol. 2003;14:578-83. [PMID: 12875416]44. Evonich RF, Maheshwari A, Gardiner JC, Khasnis A, Kantipudi S, Ip JH,et al. Implantable cardioverter defibrillator therapy in patients with ischemic ornon-ischemic cardiomyopathy and nonsustained ventricular tachycardia. J IntervCard Electrophysiol. 2004;11:59-65. [PMID: 15273456]45. Gaita F, Bocchiardo M, Porciani MC, Vivalda L, Colella A, Di Donna P,et al. Should stimulation therapy for congestive heart failure be combined withdefibrillation backup? Am J Cardiol. 2000;86:165K-158K. [PMID: 11084118]46. Gatzoulis KA, Andrikopoulos GK, Apostolopoulos T, Sotiropoulos E, Zer-vopoulos G, Antoniou J, et al. Electrical storm is an independent predictor ofadverse long-term outcome in the era of implantable defibrillator therapy. Eu-ropace. 2005;7:184-92. [PMID: 15763536]47. Greenberg D, Katz A, Epstein M, Golovchiner G, Ilia R, Caspi A. Implant-able cardioverter defibrillators in Israel: utilization and implantation trends. Int JCardiol. 2002;82:17-23. [PMID: 11786153]48. Grimm W, Hoffmann JJ, Muller HH, Maisch B. Implantable defibrillatorevent rates in patients with idiopathic dilated cardiomyopathy, nonsustained ven-tricular tachycardia on Holter and a left ventricular ejection fraction below 30%.J Am Coll Cardiol. 2002;39:780-7. [PMID: 11869841]49. Ho AT, Pai SM, Timothy P, Pai RG. Effect of concomitant antiarrhythmictherapy on survival in patients with implantable cardioverter defibrillators. PacingClin Electrophysiol. 2005;28:647-53. [PMID: 16008799]50. Koplan BA, Epstein LM, Albert CM, Stevenson WG. Survival in octoge-narians receiving implantable defibrillators. Am Heart J. 2006;152:714-9.[PMID: 16996846]51. Lampert R, McPherson CA, Clancy JF, Caulin-Glaser TL, Rosenfeld LE,Batsford WP. Gender differences in ventricular arrhythmia recurrence in patientswith coronary artery disease and implantable cardioverter-defibrillators. J Am CollCardiol. 2004;43:2293-9. [PMID: 15193696]52. Leosdottir M, Reimarsdottir G, Gottskalksson G, Torfason B, VigfusdottirM, Arnar DO. The use of implantable cardioverter defibrillators in Iceland: aretrospective population based study. BMC Cardiovasc Disord. 2006;6:22.[PMID: 16723025]53. Nazarian S, Maisel WH, Miles JS, Tsang S, Stevenson LW, StevensonWG. Impact of implantable cardioverter defibrillators on survival and recurrenthospitalization in advanced heart failure. Am Heart J. 2005;150:955-60. [PMID:16290971]54. Noseworthy PA, Lashevsky I, Dorian P, Greene M, Cvitkovic S, NewmanD. Feasibility of implantable cardioverter defibrillator use in elderly patients: acase series of octogenarians. Pacing Clin Electrophysiol. 2004;27:373-8. [PMID:15009867]55. Pappone C, Vicedomini G, Augello G, Mazzone P, Nardi S, Rosanio S.Combining electrical therapies for advanced heart failure: the Milan experiencewith biventricular pacing-defibrillation backup combination for primary preven-tion of sudden cardiac death. Am J Cardiol. 2003;91:74F-80F. [PMID:12729853]56. Parkash R, Stevenson WG, Epstein LM, Maisel WH. Predicting early mor-tality after implantable defibrillator implantation: a clinical risk score for optimalpatient selection. Am Heart J. 2006;151:397-403. [PMID: 16442906]57. Pires LA, Sethuraman B, Guduguntla VD, Todd KM, Yamasaki H, Ravi S.Outcome of women versus men with ventricular tachyarrhythmias treated withthe implantable cardioverter defibrillator. J Cardiovasc Electrophysiol. 2002;13:563-8. [PMID: 12108497]58. Pires LA, Johnson KM. Intraoperative testing of the implantable cardio-verter-defibrillator: how much is enough? J Cardiovasc Electrophysiol. 2006;17:140-5. [PMID: 16533250]59. Raitt MH, Connor WE, Morris C, Kron J, Halperin B, Chugh SS, et al.Fish oil supplementation and risk of ventricular tachycardia and ventricular fibril-lation in patients with implantable defibrillators: a randomized controlled trial.JAMA. 2005;293:2884-91. [PMID: 15956633]60. Raviele A, Bongiorni MG, Brignole M, Cappato R, Capucci A, Gaita F,et al.; BEST � ICD Trial Investigators. Early EPS/ICD strategy in survivors ofacute myocardial infarction with severe left ventricular dysfunction on optimalbeta-blocker treatment. The BEta-blocker STrategy plus ICD trial. Europace.2005;7:327-37. [PMID: 16028343]61. Rienstra M, Smit MD, Nieuwland W, Tan ES, Wiesfeld AC, AnthonioRL, et al. Persistent atrial fibrillation is associated with appropriate shocks andheart failure in patients with left ventricular dysfunction treated with an implant-able cardioverter defibrillator. Am Heart J. 2007;153:120-6. [PMID: 17174649]

62. Robin J, Weinberg K, Tiongson J, Carnethon M, Reddy M, Ciaccio C, etal. Renal dialysis as a risk factor for appropriate therapies and mortality in im-plantable cardioverter-defibrillator recipients. Heart Rhythm. 2006;3:1196-201.[PMID: 17018351]63. Russo AM, Nayak H, Verdino R, Springman J, Gerstenfeld E, Hsia H, etal. Implantable cardioverter defibrillator events in patients with asymptomaticnonsustained ventricular tachycardia: is device implantation justified? Pacing ClinElectrophysiol. 2003;26:2289-95. [PMID: 14675014]64. Saba S, Atiga WL, Barrington W, Ganz LI, Kormos RL, MacGowan GA,et al. Selected patients listed for cardiac transplantation may benefit from defi-brillator implantation regardless of an established indication. J Heart Lung Trans-plant. 2003;22:411-8. [PMID: 12681418]65. Sanchez JM, Katsiyiannis WT, Gage BF, Chen J, Faddis MN, Gleva MJ, etal. Implantable cardioverter-defibrillator therapy improves long-term survival inpatients with unexplained syncope, cardiomyopathy, and a negative electrophysi-ologic study. Heart Rhythm. 2005;2:367-73. [PMID: 15851337]66. Sanchez JM, Greenberg SL, Chen J, Gleva MJ, Lindsay BD, Smith TW, etal. Smokers are at markedly increased risk of appropriate defibrillator shocks in aprimary prevention population. Heart Rhythm. 2006;3:443-9. [PMID:16567292]67. Schaer BA, Ammann P, Sticherling C, Zellweger MJ, Cron TA, Osswald S.Prophylactic implantable cardioverter defibrillator therapy in dilated cardiomyop-athy: impact of left ventricular function. Int J Cardiol. 2006;108:26-30. [PMID:16516695]68. Sears SF, Serber ER, Lewis TS, Walker RL, Conners N, Lee JT, et al. Dopositive health expectations and optimism relate to quality-of-life outcomes forthe patient with an implantable cardioverter defibrillator? J Cardiopulm Rehabil.2004;24:324-31. [PMID: 15602153]69. Soundarraj D, Thakur RK, Gardiner JC, Khasnis A, Jongnarangsin K.Inappropriate ICD therapy: does device configuration make a difference. PacingClin Electrophysiol. 2006;29:810-5. [PMID: 16922995]70. Takahashi T, Bhandari AK, Watanuki M, Cannom DS, Sakurada H,Hiraoka M. High incidence of device-related and lead-related complications inthe dual-chamber implantable cardioverter defibrillator compared with the single-chamber version. Circ J. 2002;66:746-50. [PMID: 12197599]71. Tandri H, Griffith LS, Tang T, Nasir K, Zardkoohi O, Reddy CV, et al.Clinical course and long-term follow-up of patients receiving implantable cardio-verter-defibrillators. Heart Rhythm. 2006;3:762-8. [PMID: 16818202]72. Telfer EA, Mecca A, Martini M, Olshansky B. Implantable defibrillator usefor de novo ventricular tachyarrhythmias encountered after cardiac surgery. Pac-ing Clin Electrophysiol. 2002;25:951-6. [PMID: 12137348]73. Theuns DA, Szili-Torok T, Jordaens LJ. Defibrillation efficacy testing: long-term follow-up and mortality. Europace. 2005;7:509-15. [PMID: 16216750]74. Trappe HJ. Biventricular pacing therapy in patients with congestive heartfailure and ventricular tachyarrhythmias [Abstract]. Jahrestagung: Deutschen Ge-sellschaft fur Biomedizinische Technik: 2002 Sept; Karlsurhe, Germany. DtschGes Biomed Tech. 2002;243-9.75. Wase A, Basit A, Nazir R, Jamal A, Shah S, Khan T, et al. Impact of chronickidney disease upon survival among implantable cardioverter-defibrillator recipi-ents. J Interv Card Electrophysiol. 2004;11:199-204. [PMID: 15548886]76. Wilkoff BL, Ousdigian KT, Sterns LD, Wang ZJ, Wilson RD, MorganJM, et al.; EMPIRIC Trial Investigators. A comparison of empiric to physician-tailored programming of implantable cardioverter-defibrillators: results from theprospective randomized multicenter EMPIRIC trial. J Am Coll Cardiol. 2006;48:330-9. [PMID: 16843184]77. Ermis C, Lurie KG, Zhu AX, Collins J, Vanheel L, Sakaguchi S, et al.Biventricular implantable cardioverter defibrillators improve survival comparedwith biventricular pacing alone in patients with severe left ventricular dysfunc-tion. J Cardiovasc Electrophysiol. 2004;15:862-6. [PMID: 15333075]78. Zecchin M, Di Lenarda A, Proclemer A, Faganello G, Facchin D, Petz E, etal. The role of implantable cardioverter defibrillator for primary vs secondaryprevention of sudden death in patients with idiopathic dilated cardiomyopathy.Europace. 2004;6:400-6. [PMID: 15294264]79. Carlsson J, Schulte B, Erdogan A, Sperzel J, Guttler N, Schwarz T, et al.Prospective randomized comparison of two defibrillation safety margins in unipo-lar, active pectoral defibrillator therapy. Pacing Clin Electrophysiol. 2003;26:613-8. [PMID: 12710322]80. Dorian P, Borggrefe M, Al-Khalidi HR, Hohnloser SH, Brum JM, TatlaDS, et al.; SHock Inhibition Evaluation with azimiLiDe (SHIELD) Investiga-tors. Placebo-controlled, randomized clinical trial of azimilide for prevention of



ventricular tachyarrhythmias in patients with an implantable cardioverter defibril-lator. Circulation. 2004;110:3646-54. [PMID: 15533855]81. Friedman PA, McClelland RL, Bamlet WR, Acosta H, Kessler D, MungerTM, et al. Dual-chamber versus single-chamber detection enhancements for im-plantable defibrillator rhythm diagnosis: the detect supraventricular tachycardiastudy. Circulation. 2006;113:2871-9. [PMID: 16769912]82. Grimm W, Plachta E, Maisch B. Antitachycardia pacing for spontaneousrapid ventricular tachycardia in patients with prophylactic cardioverter-defibrilla-tor therapy. Pacing Clin Electrophysiol. 2006;29:759-64. [PMID: 16884513]83. Hreybe H, Ezzeddine R, Barrington W, Bazaz R, Jain S, Ngwu O, et al.Relation of advanced heart failure symptoms to risk of inappropriate defibrillatorshocks. Am J Cardiol. 2006;97:544-6. [PMID: 16461053]84. Lickfett L, Bitzen A, Arepally A, Nasir K, Wolpert C, Jeong KM, et al.Incidence of venous obstruction following insertion of an implantable cardio-verter defibrillator. A study of systematic contrast venography on patients present-ing for their first elective ICD generator replacement. Europace. 2004;6:25-31.[PMID: 14697723]85. Niehaus M, de Sousa M, Klein G, Korte T, Pfeiffer D, Walles T, et al.Chronic experiences with a single lead dual chamber implantable cardioverterdefibrillator system. Pacing Clin Electrophysiol. 2003;26:1937-43. [PMID:14516332]86. Saeed M, Jin A, Pontone G, Higgins S, Gold M, Harari D, et al.; LESSInvestigators. Prevalence of sensing abnormalities in dual chamber implantablecardioverter defibrillators. Ann Noninvasive Electrocardiol. 2003;8:219-26.[PMID: 14510657]87. Theuns DA, Klootwijk AP, Goedhart DM, Jordaens LJ. Prevention ofinappropriate therapy in implantable cardioverter-defibrillators: results of a pro-spective, randomized study of tachyarrhythmia detection algorithms. J Am CollCardiol. 2004;44:2362-7. [PMID: 15607399]88. Theuns DA, Klootwijk AP, Simoons ML, Jordaens LJ. Clinical variablespredicting inappropriate use of implantable cardioverter-defibrillator in patientswith coronary heart disease or nonischemic dilated cardiomyopathy. Am J Car-diol. 2005;95:271-4. [PMID: 15642568]89. Tiroke A, Ganeeva ON, Syrkin AL. [Unmotivated malfunction of implantedcardioverter-defibrillator and ways of its correction]. Klin Med (Mosk). 2003;81:26-30. [PMID: 12856564]90. Al-Khatib SM, Lucas FL, Jollis JG, Malenka DJ, Wennberg DE. Therelation between patients’ outcomes and the volume of cardioverter-defibrillatorimplantation procedures performed by physicians treating Medicare beneficiaries.J Am Coll Cardiol. 2005;46:1536-40. [PMID: 16226180]91. Bansch D, Steffgen F, Gronefeld G, Wolpert C, Bocker D, Mletzko RU, etal. The 1 � 1 trial: a prospective trial of a dual- versus a single-chamber implant-able defibrillator in patients with slow ventricular tachycardias. Circulation. 2004;110:1022-9. [PMID: 15326069]92. Boriani G, Wollmann C, Biffi M, Kuhl M, Schuchert A, Sperzel J, et al.Evaluation of a dual chamber implantable cardioverter defibrillator for the treat-ment of atrial and ventricular arrhythmias. Pacing Clin Electrophysiol. 2003;26:461-5. [PMID: 12687868]93. Brockes C, Rahn-Schonbeck 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 in3344 patients with implantable cardioverter defibrillators: results fron the Ger-man 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 to1995. Am Heart J. 2002;144:397-403. [PMID: 12228775]96. Nademanee K, Veerakul G, Mower M, Likittanasombat K, KrittayapongR, Bhuripanyo K, et al. Defibrillator Versus beta-Blockers for UnexplainedDeath 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, CullerSD, et al. The frequency and incremental cost of major complications amongmedicare beneficiaries receiving implantable cardioverter-defibrillators. J Am CollCardiol. 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 pro-

spective multicenter study. European 7219 Jewel ICD investigators. Circulation.1998;98:663-70. [PMID: 9715859]99. Schlapfer J, Rapp F, Kappenberger L, Fromer M. Electrophysiologicallyguided amiodarone therapy versus the implantable cardioverter-defibrillator forsustained ventricular tachyarrhythmias after myocardial infarction: results of long-term 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 adefibrillation lead with a small geometric electrode surface for high-impedancepacing. 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 cardio-verter defibrillator surgery: influence of patient morbidity, operation strategy, andperioperative antiplatelet/anticoagulation therapy. Chest. 2004;126:1177-86.[PMID: 15486380]102. Stevenson LW. Implantable cardioverter-defibrillators for primary preven-tion 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 MHet al. Mortality after appropriate and inappropriate shocks in ScD-HeFT [Ab-stract]. Heart Rhythm. 2006;3:S40.104. Multicenter Automatic Defibrillator Implantation Trial II. Health-relatedquality of life consequences of implantable cardioverter defibrillators: results fromMADIT 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). AmHeart J. 2002;144:282-9. [PMID: 12177646]106. Sears SF Jr, Todaro JF, Lewis TS, Sotile W, Conti JB. Examining thepsychosocial impact of implantable cardioverter defibrillators: a literature review.Clin Cardiol. 1999;22:481-9. [PMID: 10410293]107. Carroll DL, Hamilton GA. Quality of life in implanted cardioverter defi-brillator recipients: the impact of a device shock. Heart Lung. 2005;34:169-78.[PMID: 16015221]108. Sneed NV, Finch NJ, Leman RB. The impact of device recall on patientsand family members of patients with automatic implantable cardioverter defibril-lators. Heart Lung. 1994;23:317-22. [PMID: 7960857]109. Late-Breaking Clinical Trial News Release 10. Non-invasive test to predictsudden cardiac death proven effective. American Heart Association Scientific Ses-sions Late-Breaking News. 15 November 2006. Chicago: Amer Heart Assoc;2006. Accessed at http://scientificsessions.americanheart.org/portal/scientificsessions/ss/lbctnewsrelease200610 on 2 July 2007.110. Klein G, Lissel C, Fuchs AC, Gardiwal A, Oswald H, Desousa M, et al.Predictors of VT/VF-occurrence in ICD patients: results from the PROFIT-Study. Europace. 2006;8:618-24. [PMID: 16864615]111. Moss AJ. Should everyone with an ejection fraction less than or equal to30% receive an implantable cardioverter-defibrillator? Everyone with an ejectionfraction � 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 to30% receive an implantable cardioverter-defibrillator? Not everyone with an ejec-tion fraction � or � 30% should receive an implantable cardioverter-defibrilla-tor. Circulation. 2005;111:2537-49; discussion 2537-49. [PMID: 15897357]113. Huikuri HV, Castellanos A, Myerburg RJ. Sudden death due to cardiacarrhythmias. N Engl J Med. 2001;345:1473-82. [PMID: 11794197]114. Hammill S, Phurrough S, Brindis R. The National ICD Registry: now andinto the future. Heart Rhythm. 2006;3:470-3. [PMID: 16567298]115. MADIT-II Investigators. Time dependence of defibrillator benefit aftercoronary revascularization in the Multicenter Automatic Defibrillator Implan-tation Trial (MADIT)-II. J Am Coll Cardiol. 2006;47:1811-7. [PMID:16682305]116. European Heart Rhythm Association. ACC/AHA/ESC 2006 guidelines formanagement of patients with ventricular arrhythmias and the prevention of sud-den cardiac death: a report of the American College of Cardiology/AmericanHeart Association Task Force and the European Society of Cardiology Commit-tee for Practice Guidelines (Writing Committee to Develop Guidelines for Man-agement of Patients With Ventricular Arrhythmias and the Prevention of SuddenCardiac Death). J Am Coll Cardiol. 2006;48:e247-346. [PMID: 16949478]117. Multicenter Automatic Defibrillator Implantation Trial (MADIT) II In-vestigators. Causes and consequences of heart failure after prophylactic implan-tation of a defibrillator in the multicenter automatic defibrillator implantation



trial II. Circulation. 2006;113:2810-7. [PMID: 16769917]118. Kuhlkamp V, Dornberger V, Mewis C, Suchalla R, Bosch RF, Seipel L.Clinical experience with the new detection algorithms for atrial fibrillation of adefibrillator 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, Perez-Lugones A, et al. Frequency and associations of symptomatic deterioration afterdual-chamber defibrillator implantation in patients with ischemic or idiopathicdilated 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 overconventional single chamber cardioverter defibrillators in reducing inappropriatetherapies? 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 implant-able 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, AndrewsML, et al. Differences in outcomes between patients treated with single- versusdual-chamber implantable cardioverter defibrillators: a substudy of the Multi-center Automatic Defibrillator Implantation Trial II. Ann Noninvasive Electro-cardiol. 2005;10:429-35. [PMID: 16255753]123. Hughes S. DATAS restores confidence in dual-chamber ICDs. 21 July2006. 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 Forceon Practice Guidelines/North American Society for Pacing and Electrophysiol-ogy Committee to Update the 1998 Pacemaker Guidelines. ACC/AHA/NASPE 2002 guideline update for implantation of cardiac pacemakers and anti-arrhythmia 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-defi-brillator generators. JAMA. 2001;286:793-9. [PMID: 11497532]126. Al-Khatib SM, Anstrom KJ, Eisenstein EL, Peterson ED, Jollis JG, MarkDB, et al. Clinical and economic implications of the Multicenter AutomaticDefibrillator Implantation Trial-II. Ann Intern Med. 2005;142:593-600. [PMID:15838065]127. Zwanziger J, Hall WJ, Dick AW, Zhao H, Mushlin AI, Hahn RM, et al.The cost effectiveness of implantable cardioverter-defibrillators: results from theMulticenter Automatic Defibrillator Implantation Trial (MADIT)-II. J Am CollCardiol. 2006;47:2310-8. [PMID: 16750701]128. Sanders GD, Hlatky MA, Owens DK. Cost-effectiveness of implant-able cardioverter-defibrillators. N Engl J Med. 2005;353:1471-80. [PMID:16207849]129. SCD-HeFT Investigators. Cost-effectiveness of defibrillator therapy or ami-odarone in chronic stable heart failure: results from the Sudden Cardiac Deathin Heart Failure Trial (SCD-HeFT). Circulation. 2006;114:135-42. [PMID:16818817]130. Hartling L, McAlister FA, Rowe BH, Ezekowitz J, Friesen C, Klassen TP.Challenges in systematic reviews of therapeutic devices and procedures. Ann In-tern 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 cardioverter-defibrillators over a period of �10 years. Circulation. 2007;115:2474-80.[PMID: 17470696]132. Myerburg RJ, Castellanos A. Clinical research designs and implantabledefibrillator indications: spend in the beginning or pay at the end [Editorial]. JAm 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 anyof the following formats: EndNote, Reference Manager, ProCite, BibTeX,or Medlar.



Current Author Addresses: Dr. Ezekowitz: 2C2 Cardiology WMC,University of Alberta Hospital, 8440 112th Street, Edmonton, AlbertaT6G 2B7, Canada.Dr. Rowe: Department of Emergency Medicine, University of AlbertaHospital, 1G1.42, 8440 112th Street, Edmonton, Alberta T6G 2B7,Canada.Dr. Dryden, Ms. Hooton, Mr. Vandermeer, and Ms. Spooner: Univer-sity of Alberta Evidence Based Practice Center, Aberhart Centre, 11402University Avenue, Edmonton, Alberta, T6G 2J3, Canada.Dr. McAlister: University of Alberta Hospital, 2E3.24 WMC, 8440112th Street, Edmonton, Alberta T6G 2R7, Canada.

Appendix Table 1. Description of Randomized Trials Included in the Review*

Author, Trial Name, Year(Reference)

Design,Duration

Study Group PatientsRandomlyAssigned,n

Men, n(%)

Mean Age (SD), y Mean LVEF (SD) IschemicHeartDisease,%

NYHA Class, %

II III IV

Primary preventionMoss et al., MADIT, 1996 (14) RCT, 27 mo ICD 95 87 (92) 62 (9) 27 (7) 34 II or III 5 63 0

OPT 101 93 (92) 64 (9) 25 (7) 29 II or III 5 67 0Bigger, CABG Patch,

1997 (15)RCT, 32 mo CABG 1 ICD 446 386 (86.5) 64 (9) 27 (6) 100 II or III 5 71 NR

CABG 454 373 (82.2) 63 (9) 27 (6) 100 II or III 5 74 NRMoss et al., MADIT II,

2002 (16)RCT, 20 mo ICD 742 623 (84) 64 (10) 23 (5) 100 35 25 5

OPT 490 417 (85) 65 (10) 23 (6) 100 34 23 4Bansch et al., CAT, 2002 (17) RCT, 66 mo All 104 83 (79.8) 52 (11) 24 (7) 0 65.3 34.6 0

ICD 50 43 (86) 52 (12) 24 (6) 0 66.7 33.3 0OPT 54 40 (74) 52 (10) 25 (8) 0 64.1 35.8 0

Strickberger et al., AMIOVIRT,2003 (18)

RCT, 2 y All 103 72 (69.9) 59 (11) 22 (9) 0 64 19.4 0

ICD 51 34 (67) 58 (11) 22 (10) 0 64 16 0Amiodarone 52 38 (74) 60 (12) 23 (8) 0 63 24 0

Bristow et al., COMPANION,2004 (19)

RCT, 15 mo CRT 1 OPT 617 413 (67) Median, 67 Median, 20 54 Excluded 87 13

CRT 1 ICD1 OPT

595 399 (67) Median, 66 Median, 22 55 Excluded 86 14

OPT only 308 213 (69) Median, 68 Median, 22 59 Excluded 82 18Kadish et al., DEFINITE,

2004 (20)RCT, 29 mo All 458 326 (71.2) 58 (range, 20–84) 21.4 (range, 7–35) 0 57.4 21 0

ICD 229 166 (72.5) 58 (range, 20–84) 20.9 (range, 7–35) 0 54.2 20.5 0OPT 229 160 (69.9) 58 (range, 22–79) 21.8 (range,

10–35)0 60.7 21.4 0

Hohnloser et al., DINAMIT,2004 (21)

RCT, 30 mo ICD 332 252 (75.9) 61.5 (10.9) 28 (5) 100 NR NR 0

OPT 342 262 (76.6) 62.1 (10.6) 28 (5) 100 NR NR 0Bardy et al., SCD-HeFT,

2005 (22)RCT, 46 mo

(median)ICD 829 639 (76) Median, 60 (IQR,

52–69)Median, 25 52 71 29 0

Amiodarone 845 639 (77) Median, 60 (IQR,52–68)

Median, 25 50 70 30 0

Placebo 847 655 (77) Median, 59.7(IQR, 51–68)

Median, 25 53 68 32 0

Secondary preventionAVID, 1997 (23) RCT, 18 mo ICD 505 395 (78) 65 (11) 32 (13) 81 I or II 5 48 7 0

Antiarrhythmic 509 412 (81) 65 (10) 31 (13) 81 I or II 5 48 12 0Connolly et al., CIDS,

2000 (24)RCT, 35 mo ICD 328 280 (85.4) 63.3 (9.2) NR 82.2 I or II 5 37.8 III or IV 5

11.0Amiodarone 331 277 (83.7) 63.8 (9.9) NR 82.9 I or II 5 39.9 III or IV 5

10.6Kuck et al., CASH, 2000 (25) RCT, 57 mo ICD 99 78 (79) 58 (11) 46 (19) 73 59 18 0

MetoprololAmiodarone

9792

152 (80) 57.5 (10) 46 (17) 73.5 56 16 0

* AMIOVIRT 5 Amiodarone vs. Implantable Defibrillator Randomized Trial; AVID 5 Antiarrhythmics Versus Defibrillators; CABG 5 coronary artery bypass graft;CABG Patch 5 Coronary Artery Bypass Graft Patch Trial; CASH 5 Cardiac Arrest Study Hamburg; CAT 5 Cardiomyopathy Trial; CIDS 5 Canadian ImplantableDefibrillator Study; COMPANION 5 Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure Trial; CRT 5 cardiac resynchronization therapy;DEFINITE 5 Defibrillators in Non-Ischemic Cardiomyopathy Treatment Evaluation; DINAMIT 5 Defibrillator in Acute Myocardial Infarction Trial; ICD 5 implantablecardioverter defibrillator; IQR 5 interquartile range; LVEF 5 left ventricular ejection fraction; MADIT 5 Multicenter Automatic Defibrillator Implantation Trial; NR 5not reported; NYHA 5 New York Heart Association; OPT 5 optimal pharmacologic therapy; RCT 5 randomized, controlled trial; SCD-HeFT 5 Sudden Cardiac Deathin 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*

Author, Trial Name, Year (Reference) Design Duration, mo Study Group Sample Size, n Men, n (%) Mean Age (SD), y Ischemic Heart Disease, % NYHA Class, % Mean LVEF (SD)

II III IV

Alter et al., 2005 (26) Prospective cohort 46 ICD 440 357 (81.1) 58 (14) 48 49 37.3 2 34 (15)AVID, 1997 (23) RCT 18 ICD 1885 395 (78) 65 (11) 81 I or II 5 48 7 0 32 (13)

Antiarrhythmic 412 (81) 65 (10) 81 I or II 5 48 12 0 31 (13)Backenkohler et al., 2005 (27) Prospective cohort 48 All participants 245 196 (80) 62.8 (0.8) 75.1 NR NR NR 35.6 (15.4)

Secondary prevention 157 (78) 63 (11) 73.8 NR NR NR 36 (16)Primary prevention 39 (91) 62 (10) 81 NR NR NR 34 (12)

Bansch et al., CAT, 2002 (17) RCT 66 All participants 104 83 (79.8) 52 (11) 0 65.3 34.6 0 24 (7)ICD 43 (86) 52 (12) 0 66.7 33.3 0 24 (6)Control 40 (74.1) 52 (10) 0 64.1 35.8 0 25 (8)

Bardy et al., SCD-HeFT, 2005 (22) RCT 46 ICD 2521 639 (77) Median, 60.1 (IQR, 51.9–69.2) 52 57.4 21.0 Excluded Median, 24.0 (IQR, 19.0–30.0)Amiodarone 639 (76) Median, 60.4 (IQR, 61.7–68.3) 50 54.2 21.5 Excluded Median, 25.0 (IQR, 20.0–30.0)

Bigger, CABG Patch, 1997 (15) RCT 32 CABG 1 ICD 1055 386 (86.5) 64 (9) 100 II or III 5 71 0 27 (6) NRCABG 373 (82.2) 63 (9) 100 II or III 5 74 0 27 (6) NR

Blangy et al., 2003 (28) Retrospective cohort 25 Participants with LVEF #0.35 283 124 (86.1) 60.5 (11.9) 72.9 NR NR NR 27 (5)Bode-Schnurbus et al., 2003 (29) Prospective cohort 24 All participants 603 132 (80) 61.8 (9.7) 72.7 0 100 0 32.5 (13.6)Bokhari et al., CIDS, 2004 (30) Prospective cohort 132 ICD 120 50 (83) 64 (9.2) 80 I or II 5 95 III or IV 5 5 33.9 (12.5) NR

Amiodarone 50 (83) 64 (8.7) 80 I or II 5 95 III or IV 5 5 32.1 (11.1) NRBristow et al., COMPANION, 2004 (19) RCT 15 CRT 1 OPT 1520 413 (67) Median, 67 54 Excluded 87 13 Median, 20

CRT 1 ICD 1 OPT 399 (67) Median, 66 55 Excluded 86 14 Median, 22OPT only 213 (69) Median, 68 59 Excluded 82 18 Median, 22

Bruch et al., 2006 (31) Prospective cohort 12 All participants 98 67 (80) 60 (12) 74 2.7 (0.5) 29 (10) NR NRBrunckhorst, 2004 (32) Prospective cohort 12 All participants 104 97 (93.3) 67 (10) 100 NR NR NR 35 (15)Buxton et al., MUSTT, 1999 (33) RCT 39 EP–Antiarrhythmics 2202 316 (90) Median, 67 (IQR, 60–72) 96 39 24 0 Median, 30 (IQR, 20–35)

No antiarrhythmics 318 (90) Median, 66 (IQR, 58–72) 93 38 25 0 Median, 29 (IQR, 22–35)Capoferri et al., 2004 (34) Prospective cohort 20 Secondary prevention 100 NR 55 (13) 70 NR NR NR 35 (13)

Primary prevention NR 49 (15) 67 NR NR NR 36 (13)All participants NR 53 (13.9) 69 NR NR NR 35.3 (12.9)

Carlsson et al., 2003 (79) RCT NR All participants 96 86 (90) 61 (10.3) 67.7 NR NR NR 34.1 (13.2)Chan and Hayward, 2005 (35) Prospective cohort 60 ICD 6996 NR 66.2 100 NR NR NR NR

Control NR 68.6 100 NR NR NR NRChan et al., 2006 (36) Prospective cohort 27 ICD 395 339 (86) 66 (9.9) 100 NR NR NR 26.2 (6.0)Connolly et al., CIDS, 2000 (24) RCT 35 ICD 659 280 (85.4) 63.3 (9.2) 82.2 I or II 5 37.8 III or IV 5 11 34.3 (14.5) NR

Amiodarone 277 (83.7) 63.8 (9.9) 82.9 I or II 5 39.9 III or IV 5 10.6 33.3 (14.1) NRCuesta et al., 2003 (37) Prospective cohort 30 All participants 120 115 (95.8) 63.3 (9) 66.7 NR III or IV 5 22.5 33.7 (10.9) NRDorian et al., ASTRID, 2004 (38) RCT 12 All participants 149 124 (83.2) 60 (13) 71.1 51.7 9.5 0 35 (15)Dorian et al., SHIELD, 2004 (80) RCT 12 Placebo group 214 199 (93) 62 (12) NR 43 9 Excluded 34 (14)Dubner et al., 2005 (39) Retrospective cohort 27 All participants 770 578 (75) 60 (13) 39.7 I or II 5 81 III or IV 5 19 37.7 (14.3) NRDuray et al., 2005 (40) Retrospective cohort 26 All participants 375 309 (82) 63.6 (10) 84 43.5 III or IV 5 23.5 32.8 (11.4) NRElhendy et al., 2005 (41) Prospective cohort 34 ICD 90 63 (70) 65 (13) 48.9 NR NR NR 33.7 (11.9)Ellenbogen et al., 2003 (42) Prospective cohort 69 ICD 74 58 (78.4) 62 (16) 65 NR NR NR 34 (11)Ermis et al., 2003 (43) Retrospective cohort 15 All participants 310 231 (74.5) 49.3 (11.9) 45.2 15.8 58.4 18.7 NR

ICD 40 (67.8) 51.1 (9.9) 44.1 13.6 61 25.4 18.7 (6.8)No ICD 191 (76.1) 48.9 (12.3) 45.4 16.3 57.8 17.1 20.8 (9.8)

Ermis et al., 2004 (77) Prospective cohort 57 All participants 158 96 (76.1) 69 (11.5) 56 NR III or IV 5 87 NR 22 (8.7)Evonich et al., 2004 (44) Retrospective cohort 72 All participants 153 122 (79.7) 65.6 (12.6) 64.4 34 44 0 25.4 (9.01)Friedman et al., 2006 (81) RCT 6 ICD (dual-chamber) 400 163 (81) 64.3 (11.3) 81 NR NR NR 32 (13)

ICD (ventricular only) 156 (78) 65.1 (11.3) 81 NR NR NR 32 (13)Gaita et al., 2000 (45) Prospective cohort 12 All participants 96 88 (92) 66 (8) NR II, III, or IV 5 100 22 (6) NR NRGatzoulis et al., 2005 (46) Prospective cohort 33 All participants 169 142 (84) 59.9 (12.5) 60 NR NR NR 34.2 (14)

Primary prevention 18 (100) 57 (18) 78 NR NR NR 28 (10)Secondary prevention 124 (82.1) 61 (12) 58 NR NR NR 35 (14)

Greenberg et al., 2002 (47) Retrospective cohort 31 All participants 732 630 (86) 62.6 (12.4) 79 NR NR NR 29.2 (11.2)Grimm et al., 2002 (48) Prospective cohort 35 All participants 101 82 (81) 51 (14) NR 61 35 0 25 (8)Grimm et al., 2006 (82) Retrospective cohort 38 All participants 93 83 (89) 56 (13) 34.4 38 58 4 NRHo et al., 2005 (49) Retrospective cohort 53 ICD 360 288 (80) 62 (13) 68 NR NR NR 33 (17)Hohnloser et al., DINAMIT, 2004 (21) RCT 30 ICD 674 252 (75.9) 61.5 (10.9) 100 95 40 Excluded 28 (5)

Control 262 (76.6) 62.1 (10.6) 100 98 49 Excluded 28 (5)Hreybe et al., 2006 (83) Prospective cohort 48 All participants 230 181 (79) 63 (14) 75 NR III or IV 5 45 17 26 (13)Kadish et al., DEFINITE, 2004 (20) RCT 29 All participants 458 326 (71.2) 58.3 (range, 20.3–83.9) 0 57 21 Excluded 21.4 (range, 7–35)

ICD 166 (72.5) 58.4 (range, 20.3–83.9) 0 54 21 Excluded 20.9 (range, 7–35)Control 160 (69.9) 58.1 (range, 21.8–78.7) 0 61 21 Excluded 21.8 (range, 10–35)

Koplan et al., 2006 (50) Retrospective cohort 40 All participants 348 285 (82) 70 (8) 80.6 NR NR NR 30 (11)Kuck et al., CASH, 2000 (25) RCT 57 ICD 293 78 (79) 58 (11) 73 59 18 0 46 (19)

Antiarrhythmics 152 (80) 57.5 (10) 74 59 18 0 46 (17)Lampert et al., 2004 (51) Retrospective cohort 30 All participants 650 340 (85) 67.4 (SE 61.3) 100 NR NR NR 31.6 (SE, 61.7)Leosdottir et al., 2006 (52) Retrospective cohort 120 All participants 62 44 (71) 58 (14) 62 NR NR NR 40% #0.40Lickfett et al., 2004 (84) Retrospective cohort 47 All participants 105 87 (83) NR 65 NR NR NR 31 (7)Moss et al., MADIT, 1996 (14) RCT 27 ICD 196 87 (92) 62 (9) 34 II or III 5 63 0 NR 27 (7)

Control 93 (92) 64 (9) 29 II or III 5 67 0 NR 25 (7)Moss et al., MADIT II, 2002 (16) RCT 20 ICD 1232 623 (84) 64 (10) 100 35 25 5 23 (5)

Conventional treatment 417 (85) 65 (10) 100 34 23 4 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 Sample Size, n Men, n (%) Mean Age (SD), y Ischemic Heart Disease, % NYHA Class, % Mean LVEF (SD)

II III IV

Nazarian et al., 2005 (53) Retrospective cohort 36 All participants 94 69 (73) 55 (11) 45 20 35 33 25 (10)Niehaus et al., 2003 (85) Retrospective cohort 12 All participants 25 20 (80) 60.8 (12) 72 NR NR NR 35 (14)Noseworthy et al., 2004 (54) Retrospective cohort 84 All participants 637 169 (80) 74.9 (4.4) 80 I or II 5 90.1 NR NR 34.1 (12.1)Pappone et al., 2003 (55) Prospective cohort 28 All participants 135 102 (76) 64 (11) 43 0 III or IV 5 100 28 (6) NRParkash et al., 2006 (56) Retrospective cohort 38 All participants 469 356 (76) 65 (15) 62 # II 5 81 III or IV 5 19 31 35 (16)Pires et al., 2002 (57) Retrospective cohort 24 ICD 2030 1654 (81.5) 64.4 (12.4) 78 55 III or IV 5 19 NR 33.7 (13.8)Pires et al., 2006 (58) Retrospective cohort 22 All participants 861 641 (77) 65.4 (12.7) 57 NR NR NR 24.1 (10.4)Raitt et al., 2005 (59) RCT 120 ICD (placebo group) 100 86 (86) 62 (13) 71 14 50 8 34 (15)Raviele et al., BEST1ICD, 2005 (60) RCT 24 All participants 143 98 (71) 66.5 (9.6) 100 NR NR Excluded 31.1 (4.1)Rienstra et al., 2007 (61) Prospective cohort 31 All participants 290 231 (80) 59.9 (12.5) 72 I or II 5 88 11 ,1 29 (7.8)Robin et al., 2006 (62) Retrospective cohort 132 All participants 585 462 (79) 63 (15) 60 NR NR NR 33 (15)Russo et al., 2003 (63) Prospective cohort 16 All participants 51 41 (92) 70 (9) (range, 41–98) 100 NR NR NR 29 (9)Saba et al., 2003 (64) Retrospective cohort 48 ICD 35 29 (82.9) 51 (12) 20 Excluded III or IV 5 100 17 21.9 (6.8)

Control 114 (71.7) 51 (12) 73 Excluded III or IV 5 100 26 22.1 (9.7)Saeed et al., LESS, 2003 (86) Prospective cohort 8 All participants 229 38 (79) 64 (12) 63 42 23 0 33.6 (14.8)Sanchez et al., 2005 (65) Case–control NR ICD 102 15 (79) 60 (16) 47 NR NR Excluded 27 (7)

Conventional therapy 26 (81) 61 (13) 59 NR NR Excluded 27 (6)Sanchez et al., 2006 (66) Retrospective cohort 22 All participants 123 93 (89) 66.7 (9.3) 100 NR NR NR 26.6 (7.7)Schaer et al., 2006 (67) Prospective cohort 18 All participants 58 50 (86) 56.4 (12.7) 0 NR NR NR 25 (8.8)Sears et al., 2004 (68) Prospective cohort 14 All participants 88 73 (83) 65 (13) 69 NR NR NR 30.5 (16.4)Soundarraj et al., 2006 (69) Retrospective cohort 2 All 386 297 (77) 67 (11) 81 NR NR NR 26.2 (8.9)

ICD (single-chamber) 295 226 (77) 68 (11) 83 26.4 (9.1)ICD (dual-chamber) 91 71 (78) 66 (11) 75 25.6 (8.3)

Takahashi et al., 2002 (70) Retrospective cohort 12 All participants 178 144 (81) 64 61 NR NR NR 33 (15)Tandri et al., 2006 (71) Retrospective cohort 276 All participants 1382 1050 (76) 62 (11) 72 38 III or IV 5 23 NR 33 (11)Telfer et al., 2002 (72) Retrospective cohort 26 ICD 379 26 (96) 59 (13) NR NR NR NR 22 (7)Theuns et al., 2004 (87) RCT 12 ICD (single-chamber) 60 24 (83) 57 (17) 72 NR NR NR 29 (11)

ICD (dual-chamber) 23 (74) 61 (10) 84 NR NR NR 31 (10)All participants 47 (78) 59 (14) 78 NR NR NR 30 (10.5)

Theuns et al., 2005 (88) Prospective cohort 60 All participants 127 216 (83) 60 (13) 71 NR NR NR 31 (14)Theuns et al., 2005 (73) Prospective cohort 48 All participants 326 105 (83) 59 (11) 72 I or II 5 72 III or IV 5 28 0 35 (15)Tiroke et al., 2003 (89) Retrospective cohort 60 All participants 149 136 (91.3) 62 (range, 51–72) 77 42 38 2 NRTrappe, 2002 (74) Prospective cohort 28 All participants 410 368 (89.8) 57 (11) NR I or II 5 12

II 5 37II or III 5 29III 5 22

0 NR

Wase et al., 2004 (75) Retrospective cohort 48 ICD 256 66 (71) 66.5 (12.2) NR NR NR NR 29 (12.5)Wilkoff et al., EMPIRIC, 2006 (78) RCT 12 All participants 900 731 (81.2) 65 (12.6) 69.4 I or II 5 47 III or IV 5 14.5 0 32.0 (12.7)Zecchin et al., 2004 (78) Retrospective cohort 24 All participants 54 43 (79.6) 52.5 (17.2) 0 I or II 5 76 NR NR 26.5 (7.6)

Non-LVSD (for peri-implantation safetyonly)

Al-Khatib et al., 2005 (90) Retrospective cohort 33 ICD 9854 7724 (78.4) NR NR NR NR NR NRBansch et al., 2004 (91) RCT 12 ICD 102 NR NR 82.4 58.8 16.6 0 37.5 (13.5)Boriani et al., 2003 (92) RCT 6 ICD 89 69 (77.5) 64.1 (12.5) 60 60 NR NR 46 (16)Brockes et al., 2002 (93) Retrospective cohort 72 ICD 130 115 (88.5) 61 (11) 100 NR NR NR 36 (12)Gradaus et al., 2003 (94) Retrospective cohort 34 ICD 3344 2682 (80.2) 61.1 (12.1) 64.6 54.3 20.9 1.1 70.6% .0.30Hlatky et al., 2002 (95) Retrospective cohort 84 ICD 22 565 18 255 (80.9) 71.5 6 NR NR NR NRNademanee et al., DEBUT, 2003 (96) RCT 36 ICD 47 45 (95.7) 40.9 (11) NR 0 0 0 66.1 (10.3)Reynolds et al., 2006 (97) Retrospective cohort 12 ICD 30 984 24 401 (78.8) NR NR NR NR NR NRRosenqvist et al., 1998 (98) Prospective cohort 4 ICD 778 635 (81.6) 58 (13) 58 53.3 23.1 0.9 39 (17)Schlapfer et al., 2002 (99) Prospective cohort 63 ICD 41 7724 (78.4) NR NR NR NR NR NRVollmann et al., 2003 (100) RCT 12 ICD 542 NR NR 82.4 58.8 16.6 0 37.5 (13.5)Wiegand et al., 2004 (101) Retrospective cohort 144 ICD 372 69 (77.5) 64.1 (12.5) 60 60 NR NR 46 (16)

* ASTRID 5 Atrial Sensing Trial to prevent Inappropriate Detections; AVID 5 Antiarrhythmics Vs. Defibrillators; BEST1ICD 5 BEta-blocker STrategy plus ICD trial; CABG 5 coronary artery bypass grafting; CABG Patch 5 Coronary Artery Bypass Graft Patch Trial; CASH 5 Cardiac Arrest Study Hamburg; CAT 5 Cardiomyopathy Trial; CIDS 5 Canadian Implantable DefibrillatorStudy; COMPANION 5 Comparison of Medical Therapy, Pacing, and Defibrillation in Chronic Heart Failure Trial; CRT 5 cardiac resynchronization therapy; DEBUT 5 Defibrillator versus b-blockers for unexplained death in Thailand; DEFINITE 5 Defibrillators in Non-Ischemic Cardiomyopathy Treatment Evaluation; DINAMIT 5 Defibrillator in Acute Myocardial Infarction Trial;EMPIRIC 5 Comparison of Empiric to Physician-Tailored Programming of Implantable Cardioverter Defibrillators; EP 5 electrophysiology; ICD 5 implanted cardioverter defibrillator; IQR 5 interquartile range; LESS 5 Low-Energy Safety Study; LVEF 5 left ventricular ejection fraction; LVSD 5 left ventricular systolic dysfunction; MADIT 5 Multicenter Automatic Defibrillator ImplantationTrial; MUSTT 5 Multicenter Unsustained Tachycardia Trial; NR 5 not reported; NYHA 5 New York Heart Association; OPT 5 optimal pharmacologic therapy; RCT 5 randomized, controlled trial; SCD-HeFT 5 Sudden Cardiac Death in Heart Failure Trial; SHIELD 5 Shock Inhibition Evaluation With Azimilide.

W-50 21 August 2007 Annals of Internal Medicine Volume 147 • Number 4 www.annals.org

Systematic Review: Implantable Cardioverter Deﬁbrillators ...library.tasmc.org.il/ in LV... ·...

Documents

Transcript of Systematic Review: Implantable Cardioverter Deﬁbrillators ...library.tasmc.org.il/ in LV... ·...