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Journal of the American College of Cardiology Vol. 51, No. 21, 2008© 2008 by the American College of Cardiology Foundation ISSN 0735-1097/08/$34.00P

YEAR IN CARDIOLOGY SERIES

The Year in Review ofClinical Cardiac Electrophysiology

Melvin M. Scheinman, MD, FACC,* Edmund Keung, MD†

San Francisco, California

ublished by Elsevier Inc. doi:10.1016/j.jacc.2008.02.055

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trial Fibrillation (AF) and Atrial Flutter (AFL)

n contrast to previous years, when the emphasis was on these of ablative therapy for the treatment of atrial fibrillation,007 has brought about renewed interest in drug-treatmentrials for patients with AF or AFL. The AF-CHF (Atrialibrillation in Congestive Heart Failure) trial was reportedt the annual American Heart Association (AHA) meeting1) and are an important follow-up study to the originalFFIRM (Atrial Fibrillation Follow-up Investigation ofhythm Management) trial (2). In the AFFIRM study ofatients with AF, no benefit was observed for those treatedor rhythm control compared with those treated to achieveate control. Atrial fibrillation is common in patients withongestive heart failure (CHF) and is said to be an inde-endent risk factor for cardiac death in some (but not all)tudies. Hence, the notion that prevention of AF wouldenefit patients with CHF would be of great value. TheFFIRM trial contained relatively few patients with con-

estive heart failure, and the AF-CHF trial represents therst adequately powered randomized trial of patients withF and CHF.The AF-CHF trial was designed as a multicenter, pro-

pective study to determine whether maintenance of sinushythm reduced cardiovascular mortality compared with aate-controlled strategy in patients with CHF and AF.econdary pre-specified end points included total mortality,orsening heart failure, cerebrovascular accident, hospital-

zation, quality of life, and costs. A total of 1,376 patientsere randomized during the course of a 4-year study period.

nclusion criteria included left ventricular ejection fractionLVEF) �35% and 1 episode of documented AF within 6onths of enrollment. Atrial fibrillation was persistent in

9% of patients, and 31% were in New York Heartssociation (NYHA) functional class III to IV. Patientsere randomized to a rhythm-controlled arm and were

reated with amiodarone as the initial drug choice andotalol or dofetilide were used in selected cases. Repeatedirect current cardioversions were used to maintain sinus

rom *Cardiac Electrophysiology, University of California San Francisco, and

qVeterans Affairs Medical Center, San Francisco, California.Manuscript received February 12, 2008; accepted February 22, 2008.

hythm. The rate control group was treated with digoxinnd beta-blockers. Both groups received optimal medicalanagement for heart failure, and both groups received

nticoagulant therapy. The prevalence of sinus rhythm onollow-up examination was approximately 80% in thehythm-controlled group. No significant difference wasound in the primary outcome between the rhythm-ontrolled group versus the rate-controlled group (26.7% vs.5.5%). Similarly, there was no difference in total mortality31.8% vs. 32.9%), stroke (2.6% vs. 3.0%), or worseningeart failure (27.6% vs. 30.8%). The authors concluded thatrhythm control does not improve cardiovascular mortalityhen compared to rate control.” The results of the AF-HF trials, therefore, extend the original observation of theFFIRM trials to those with AF and CHF. There appears

o be no overriding need to maintain sinus rhythm in thisubgroup as long as rate control is achieved.

In addition, several large drug trials were reported. Forxample, 2 large-scale trials of dronedarone (a homolog ofmiodarone) for patients with AF or AFL were reported3). The 2 studies had identical protocols, but one wasonducted in Europe whereas the other was in non-uropean countries. The study protocol involved a multi-

enter, double-blind, placebo-controlled study for patientsith paroxysmal AF or AFL but without evidence of class

II or IV CHF. In both trials, the median time to arrhyth-ia recurrence was significantly greater for the treated

roups (41 days vs. 96 days for the European group and 59ays vs. 158 days for the non-Europeans). Of furthernterest was the fact that there was no difference in thencidence of adverse side effects between the treated andlacebo groups apart from a greater incidence of increasederum creatinine for the treated group. A previous trial thatsed dronedarone for patients with congestive heart failureANDROMEDA [Antiarrhythmic Trial with Dronedar-ne in Moderate-to-Severe Congestive Heart Failure Eval-ating Morbidity Decrease] trial) was terminated prema-urely because of increased mortality in the treated group.he current study did not address this important issue. In

ddition, we do not have a head-to-head comparisonetween this agent and amiodarone for this patient cohort.he lack of reported toxicity with respect to dronedarone is

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2076 Scheinman and Keung JACC Vol. 51, No. 21, 2008Year in Clinical Cardiac Electrophysiology May 27, 2008:2075–81

Vernakalant (previously RSD-1235) has been the subjectf several recent reports. Earlier trials of this agent assessingafety and efficacy (ACT [Atrial arrhythmia Conversionrial] 1 and ACT 3]) (4) included a total of 575 patients.he overall conversion rates in response to intravenous

ernakalant for those with recent-onset AF (3 h to 7 days)as 51.1% versus 38% for placebo (p � 0.0001). Theedian time to conversion ranged from 10 to 11 min. Stiell

t al. (5) reported on the safety and efficacy of a recentpen-labeled multicenter trial (ACT 4). This trial involved36 patients of AF of �3 h duration. Of this group, 167 hadF of �7 days’ duration. Of the patients with recent-onsetF (�7 days), 51% converted to sinus rhythm within aedian time of 14 min. The conversion rate for those withF of 8 days or longer was �10%. There were no reports of

entricular fibrillation or torsades in any of the reportedernakalant trials; however, nonsustained ventricular tachy-ardia (VT) was reported in 3.4% of patients within 2 h andn 6.4% at 2 to 24 h. A recent report of the AHA meetinglso documented the safety and efficacy of intravenousernakalant for patients with post-surgical AF (6).

The available data suggest that the intravenous form ofernakalant will be a welcome addition for treatment ofatients with AF. Its mode of action appears unique in thatt inhibits both the atrial ultra-rapid K� current as well asrequency-dependent Na� channels. Although its efficacy isimilar to that of ibutilide, the safety profile appears to beuperior. An oral preparation of vernakalant is in the earlytages of study.

A recent prospective randomized study by Kafkas et al.7) compared rates of conversion with sinus rhythm forhose with recent-onset AF and AFL treated with eitherntravenous amiodarone versus intravenous ibutilide. Foratients with either AF or AFL, intravenous ibutilide wasignificantly superior to amiodarone in conversion to sinushythm. This study is a potentially important one in viewf the somewhat-puzzling popularity in use of intrave-ous amiodarone for acute management of patients with AFr AFL.Researchers of a randomized prospective study (8) com-

ared the use of oral amiodarone versus cavotricuspidblation for patients with a first onset of AFL. The studyomprised 104 patients randomized to the 2 treatmentrms. The patients treated with ablation achieved signifi-antly better success in terms of maintenance of sinushythm. This study extends previous observations favoringblative therapy and extends these observations in supportor early superiority of ablative treatment.

Azimilide is an experimental agent with properties thatlock the late outward K� currents (Ikr and Iks blockade).revious studies have shown that the use of azimilide maye effective in the maintenance of sinus rhythm afterardioversion (9). In a recent oral azimilide trial, 402atients with AF/AFL (and 56 with paroxysmal supraven-ricular tachycardia) were enrolled (10). The authors found

o significant difference in time to first recurrence between f

reated patients (38 days) and the placebo group (27 days).f note was the occurrence of nonsustained VT (1 episode

f torsades) in 4 patients, all in the treated group. The studyuggests that oral azimilide would appear to have no role inhe management of patients with AF, AFL, or paroxysmalupraventricular tachycardia.

entricular Arrhythmias

he ABCD (Alternans Before Cardioverter Defibrillator)rial. The authors of early primary prevention trials usednvasive electrophysiological (EP) testing to identify high-isk individuals (11,12). This approach resulted in excellentherapeutic efficacy (4 implantable cardioverter-defibrillatorsICDs] for each life saved) (13). More recent trials wereonstructed to avoid the need for invasive testing andssessed risk on the basis of reduced left ventricular ejectionraction (14,15). On the basis of these studies, patients withn ejection fraction (EF) of �35% were found to benefitrom ICDs. Unfortunately, this approach required insertionf 15 to 17 ICDs to save one life. The rationale behind theBCD trial (which was first reported at the AHA meeting

n 2006) was to compare the relative efficacy of invasive EPesting with noninvasive microvolt alternans testing. Theatter is a noninvasive spectral approach to assess very smallmicrovolt) beat-to-beat alternans of the T waves. Previoustudies emphasized the powerful negative predictive accu-acy of microvolt T-wave alternans (MTWA) therapy16,17).

A total of 566 patients were enrolled from 43 centers.nclusion characteristics were the presence of coronaryrtery disease, LVEF �40%, and nonsustained VT (�3eats). The study was powered to test the hypothesis thatTWA was noninferior to invasive EP testing in predict-

ng events at 1 year. The study group consisted of 84% men,verage age 65 � 10 years with a mean LVEF of 0.28 �.08. The MTWA was positive in 46%, negative in 29%,nd indeterminate in 23%. The EP study was positive in9% and negative in 61%. However, discordant results wereound in 55% (i.e., MTWA�, EP�, or vice versa). A totalf 65 patients met the end point of VT, ventricularbrillation, or sudden cardiac death (10 patients).Despite the discordant results, there was no difference in

ither the positive or negative predictive accuracy comparingP-guided versus MTWA-guided therapy. The latter wasefined by an indeterminate MTWA and � EP study. Ofnterest was the finding that Kaplan-Meier event ratesomparing EP� versus EP� groups remained significantlyifferent for up to 2 years of follow-up, whereas MTWA-irected therapy proved predictive for only the first year.hey found a synergistic relationship between EP andTWA testing. The predicted event rate was markedly

mproved (12.6%) when both tests are positive and quite low2%) when both are negative or normal. The therapeuticfficacy (appropriate shock) of implanting ICDs improved

rom 7% (using LVEF alone) to 66% in those with a

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2077JACC Vol. 51, No. 21, 2008 Scheinman and KeungMay 27, 2008:2075–81 Year in Clinical Cardiac Electrophysiology

ositive EP study. Of note the efficacy of MTWA abnor-ality alone improves efficacy to 35%.The authors concluded that in patients with coronary

rtery disease, nonsustained VT, and LVEF �35% MTWAs as effective as EP for prediction of events at 1 year. Theyound that the combination of MTWA and EP wasynergistic in predicting outcome; however, the predictivealue of MTWA is dissipated in the second year ofollow-up. In contrast, Bartone et al. (18) found that aon-negative MTWA test proved to be a robust predictorf all-cause mortality for those with ischemic disease with a6-month follow-up.This represents an important prospective study because

hey were able to compare invasive with non-invasiveesting. The negative predictive value of MTWA wasupported but the positive predictive accuracy was quiteoor (Fig. 2). What are the practical implications for thelinicians? A negative test tilts toward not inserting theefibrillator but at the expense of missing a small percentagef patients who might benefit. In addition, the data empha-ize the rationale for the MTWA-directed approach (i.e.,

TWA indeterminate EP�). No technique is perfect, andhe ultimate use will be dependent on the clinical decision ofhe acceptable threshold for which patients should bereated. This, of course, is taking into account the impor-ance of age and comorbidities.

Another recent trial that focused on the use of MTWAas presented at the annual American College of Cardiol-gy meeting (19). This trial attempted to test whetherbnormal MTWA predicts life-threatening arrhythmias inMADIT (Multicenter Automatic Defibrillator Implantrial)-II population. The study included 575 patients withprior myocardial infarction and EF �30%, and the

rimary end points were appropriate ICD shocks or ar-hythmic deaths. The population showed a mean EF of4%, and most had a history of congestive heart failure.here was no significant difference in end points between

he MTWA negative patients (10%) versus those withon-negative (positive and indeterminate) (13%). Further-ore, sub-group analyses showed that those patients withRS �120 ms were at low risk regardless of MTWA result.lthough the methodology and patient population of theASTER trial differed from the ABCD trial it, neverthe-

ess, suggests caution in the use of MTWA as a risktratifier. In addition, a very thoughtful and critical appraisalf MTWA was recently published (20). They concludedhat “the evidence for the use of MTWA in risk stratifica-ion of SCD is compelling in some aspects, principally itsPV [negative predictive value] in patients with ischemicVSD [left ventricular systolic dysfunction]. However, thevailable evidence is not yet sufficient to allow its extrapo-ation to routine clinical use in large numbers of patients toetermine whether primary prevention ICD implantation is

ndicated.”Another interesting report involved a study of ranolazine

n patients with acute coronary ischemia (21). Ranolazine is g

drug that was recently approved for management ofatients with angina pectoris that is refractory to conven-ional therapy. The mechanism of the anti-ischemic actions not clear, but the effects of this drug on ion channelunction have been clarified. Ranolazine has been found toe associated with mild prolongation of the QT interval.lectrophysiological studies have shown that ranolazine acts

o block the late Na� current (which would tend to shortenhe QT) and to block Ikr current (which would tend torolong the action potential duration and QT). The Ikrffect appears to predominate because the drug is associatedith a mild QT prolonging effect. Furthermore, the effectsn the Ikr current appear to predominate in epicardial andndocardial cells, whereas the Ina block predominates inid-myocardial cells. Overall, the drug appears to decrease

ransmembrane repolarization heterogeneity. Blockage ofhe late Ina current would be expected to prevent systolica2� overload and might have antiarrhythmic properties.his reasoning was the underpinning for a recent trial,hich randomized 6,560 patients with non–ST-segment

levation myocardial infarction acute coronary syndrome toeceive either ranolazine or placebo (22). The patientsnderwent continuous electrocardiogram monitoring for 7ays after enrollment. A pre-specified set of arrhythmiasas examined in blinded fashion by the Core lab. The majorndings were a statistically significant decrease in the

ncidence of nonsustained VT lasting either 4 or 8 beats. Forhose treated with ranolazine, there was no difference in thencidence of sustained polymorphous VT compared withhose treated with active drug (0.32%) versus placebo0.22%; p � 0.46). The episodes of polymorphous VTppeared to be related to myocardial ischemia in bothroups. There was no significant difference in either totalortality or in sudden death between groups. This was

rue even for those in the highest risk groups (i.e., CHF,evere ischemia). In addition, although the incidence ofF was less for the treated group, this was not statisti-

ally significant.In summary, although the apparent finding of an antiar-

hythmic effect is of interest, this alone is of limited practicalalue. The lessons learned from CAST (Cardiac Arrhyth-ia Suppression Trial) are evident. A drug that decreases

remature ventricular complex density does not necessarilyrolong life. The neutral effect of the drug on overallortality is a testament to its safety. Its true role as an

ntiarrhythmic agent remains to be established.

ardiac Genetic Syndromes

ome of the most striking advances in clinical cardiac EPontinue to occur in the area of the genetic arrhythmiayndromes. In 2007, there was a spate of excellent basic andlinical studies further elucidating the long-QT syndromeLQTS). The latter has occurred because of the fact that0% to 80% of these patients may now be successfully

enotyped and because of the availability of a large inter-

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2078 Scheinman and Keung JACC Vol. 51, No. 21, 2008Year in Clinical Cardiac Electrophysiology May 27, 2008:2075–81

ational registry for long-QT patients (23) allowing forhenotype-genotype correlations.QTS. This syndrome was first described in 1957 by

ervell and Lange-Nielsen (24) and highlighted the associ-tion between congenital deafness, prolonged QT interval,nd sudden death. It has been determined that gain ofunction of Na� channels (encoded by SCN5A) or decreasen function of the delayed k� rectifier currents Iks (slowctivation K� current) or Ikr (rapidly activated k� current)re the main causes of the LQTS. The mutations involveither the membrane-spanning � subunits or the associatedroteins attached to these channels. The vast majority ofatients will have genetic abnormalities involving k� chan-els (Iks–LQT1), (Ikr–LQT2), or Na� channels SCN5ALQT3) (25). Rare mutations of a gene encoding the L-typea2� channel have been described.The vast majority of known mutations involve genes that

ncode Iks and Ikr channels (85%), whereas SCN5Autations make up approximately 13%. Compound muta-

ions in the same or different genes occur in as many as 10%f genotype positive groups (26) and appear to be associatedith a greater incidence of arrhythmias. A host of recent

tudies have focused on the ungenotyped 25% to 30% ofQTS patients (27–30). These studies have focused on

ntron mutations or abnormalities in the exon splice sites. Inddition, 2 newer mutations causing the LQT1 syndromeave been described, one involving the Yotiao proteinomplex (31), which produces a pattern similiar to LQT1Iks current), and the other resulting in an abnormality oflpha-1-syntrophin, which produces a LQT3 picture (32).ewer clinical findings. A number of studies have focused

n genotype-phenotype interactions. For example, in LQT2atients, mutations in the pore region of the KCNH2 genere at increased risk for cardiac arrhythmias compared withhose with nonpure mutations (33). One study focused onQT patients between the ages of 18 and 40 years and

ound that female gender, LQT2, QTc �500 ms, and theresence of cardiac events (syncope, aborted sudden death)efore the age of 18 years were associated with an increasedisk of cardiac events in adulthood (34). In contrast, maledolescents between the ages of 10 and 12 years were atreater risk than female adolescents. Similarly, QTc dura-ion and syncopal episodes were found to be risk factors forife-threatening events (35).

The beneficial effects of beta-blocker therapy have longeen appreciated. More recent observations have focused onhe fact the most pronounced beneficial effects are observedor those with LQT1 with decreased efficacy for those withQT2 and especially for those with LQT3 or the Jervell-ange-Nielsen syndrome (36), Another study focused on

he effects of pregnancy on women with LQTc (37). It wasound that the risk for cardiac events was reduced duringregnancy but that the 9-month post-partum period wasdentified as a high-risk period. However, treatment with

eta-blockers mitigated the post-partum risk. p

A recent study focused on a cohort of 27 children withQTS who were treated with a defibrillator (38). Most of

hese patients were genotyped as LQT2 or LQT3 andnderwent implantation after failed beta-blocker therapy.n follow-up, 5 (12%) had appropriate shocks and 4 had at

east 1 inappropriate shock. None had recurrent shockselectrical storm). This study highlights the emerging expe-ience of automatic ICD therapy in the high-risk pediatricopulation. It is important to set the automatic ICDischarge rate at appropriate levels for active children tovoid inappropriate shocks incident to sinus tachycardia.

Finally, important insights were gained from a retrospec-ive study in which the authors used post-mortem geneticesting on young individuals with sudden unexplainedeath. A total of 17 genetic mutations were found in 49ubjects studied (39). Ten were found to have abnormalitiesn genes associated with LQTS, and 7 had abnormalities inhe RyR2 genes responsible for the syndrome of cat-cholaminergic polymorphous ventricular tachycardia. Ad-itional studies have shown that the LQTS is implicated in% to 10% of infants with sudden infant death syndrome40–42) or in stillbirth children (43).

ardiac Rhythm and Heartailure Management Devices

riving with ICD. Patients with ICDs often ask theirhysicians whether they can continue driving. Despiteecent guidelines that suggest resumption of driving as soons the surgical incision is healed, it remains a difficult andncomfortable question because of patient and public safetyoncerns, impact on quality of life, and socioeconomic andegal ramifications. Recently, the TOVA (Triggers of Ven-ricular Arrhythmias) study provided some reassuring infor-ation on this matter when the investigators examined the

mpact of driving on ICD discharges among 1,188 ICDatients with class I and II implant indications (44). Theelative risk of shocks for VT/ventricular fibrillation wasnly significantly increased during the 30-min period afterriving. Most importantly, the risk of ICD shock was notreater during driving. Neither new implants (defined as �6onths implanted) nor indications (primary or secondary

revention) had an interactive effect on the analysis. Thetudy also pointed out that 1 in 7 patients experiencing

shock actually had an auto accident. Precise guidelinesor driving for patients with ICDs have been previouslyublished (45).ardiac resynchronization therapy (CRT). The investi-

ators of the COMPANION (Comparison of Medicalherapy, Pacing and Defibrillation in Heart Failure) studyerformed a retrospective data analysis to determinehether class IV patients would benefit from cardiac resyn-

hronization therapy with defibrillator (CRT-D, n � 83) orithout defibrillator (CRT, n � 79) when compared with

atients on optimal medical therapy (OPT, n � 55) (46).

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2079JACC Vol. 51, No. 21, 2008 Scheinman and KeungMay 27, 2008:2075–81 Year in Clinical Cardiac Electrophysiology

he studied patients had a very poor prognosis, as evidencedy a 44% mortality at the end of 1 year in the OPT group.At 2 years, when compared with OPT, both CRT and

RT-D improved: 1) the time to all-cause mortality or firstospitalization, and 2) the time to all death or heart failureospitalization. Only CRT-D benefited the time to suddeneath: 25%, 16%, and 9% died of sudden cardiac death inear 2 for OPT, CRT, and CRT-D, respectively. The resultuggested that CRT and CRT-D should be considered inmbulatory NYHA functional class IV patients with heartailure. The data confirmed once again that the ICD isffective in preventing sudden cardiac arrhythmic death evenn NYHA functional class IV patients. As therapy devicesor patients with severe heart failure, neither CRT norRT-D improved the time to heart failure death. It islausible that the ventricles were too sick to allow formprovement in mechanical performance.

Results from small and nonrandomized studies haveuggested that CRT may benefit patients with left ventric-lar mechanical dyssynchrony even in the presence oformal QRS duration. This unsettled issue was examined inrandomized nonblinded study (RethinQ: the Cardiac

esynchronization Therapy in Patients with Heart Failurend Narrow QRS) involving 172 patients with NYHAunctional class III heart failure, an EF of 0.35, QRSuration of �130 ms, and ventricular dyssynchrony docu-ented by tissue Doppler (47). One-half of the patients

eceived a CRT-D and the other half received an ICD. Atmonths, there were no differences between the 2 groups ineak oxygen consumption, quality-of-life score, 6-min walkistance, and heart failure events requiring intravenousherapy. On the basis of these results, it was concluded thatatients with heart failure and narrow QRS interval may notenefit from CRT. It remains to be seen whether this studyefines the role of CRT in patients with narrow QRSomplex. It is conceivable that the negative results wereelated to the short follow-up period and the identificationethod (M-mode echocardiography was not used in 96% of

he patients). The study was not designed to examine commonnd points such as mortality and heart failure hospitalization.CD patients and risk stratification. On the basis of aumber of multicenter clinical studies, ICD implant indi-ations have been greatly expanded since their introduction.t the same time, we have been trying to refine our patient

election criteria with the ultimate goal of implanting ICDnly in patients who will need therapy. The MUSTTMulticenter Unsustained Tachycardia Trial) investigatorsetrospectively examined their database to construct a risk-tratification model to better predict mortality risk and suddeneath in patients with coronary artery disease, LVEF �0.40,onsustained VT, and inducible ventricular sustained VT,ith the goal of improving ICD patient selection (48).The following risk factors were found to have a statisti-

ally significant association with total mortality: NYHAunctional class at the time of enrollment, left bundle branch

lock or interventricular conduction delay, history of heart t

ailure, LVEF, age, atrial fibrillation at the time of enroll-ent, inducible VT, and previous coronary artery bypass

rafting. Arrhythmic death was associated with left bundleranch block or interventricular conduction delay, heartailure, LVEF, inducible VT, nonsustained VT 10 dayseyond coronary artery bypass grafting, and patients en-olled into the study as inpatient. Using patient survival datan the MUSTT database and assigning points to each riskactor, a model was created to best predict the survival ofatients in the MUSTT database.As pointed out by the accompanying editorial, the use of

his risk-stratification model is severely limited by the facthat it is based on patients who had inducible VT by EPtudy, an approach that is rarely used in clinical practice49). Renal function, which had been identified as anndependent predictor of mortality, was not found to be aisk factor in the analysis (50). Nevertheless, the modelhowed that several other variables carried a similar prog-ostic significance as LVEF: in the absence of other riskactors, an LVEF �0.30 was associated with a 2-year totalortality of only 5%.Analysis of patients in the conventional therapy arm ofADIT-II identified 5 risk factors in predicting all-causeortality: 1) New York Heart Association functional classII; 2) age �70 years; 3) blood urea nitrogen �26 mg/dl;

) QRS duration �0.12 s; and 5) AF (51). The use of ICDherapy reduced 2-year mortality by 49% among patientsith �1 risk factor and offered no benefit in patients witho risk factor (approximately one-third of the patients,-year mortality of only 8%) and with marked renalysfunction (blood urea nitrogen �50 mg/dl and/orreatinine �2.5 mg/dl). Similar to the MUSTT analysis,he investigators observed that LVEF may not be thenly selection criterion for ICD therapy in patients withschemic cardiomyopathy.

rouble with high-voltage (HV) ICD leads. The reliabil-ty of HV defibrillator leads was called to attention by aerformance report on 990 leads implanted between 1992 to005 from a single registry (52). The survival rate wasisturbingly low: 90%, 85%, and 60% at 3, 4, and 8 years,espectively. The failure rate increased progressively withime. The adverse events included insulation defects (56%),ead fractures (12%), loss of ventricular capture (11%),bnormal lead impedance (10%), and sensing failure (10%).t is important to note that two-thirds of lead defects coulde detected by routine device interrogation, underscoringhe importance of post-implant device follow-up. Theailure rate may be overestimated because the analysisncluded complications (such as T-wave oversensing, exitlock, and R-wave under-sensing) that may not alwayselate to intrinsic lead defects. This report was soon fol-owed by a major Food and Drug Administration class Iecall of the Medtronic Fidelis (Medtronic, Minneapolis,

innesota) leads and reports on a still unsettled complica-

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2080 Scheinman and Keung JACC Vol. 51, No. 21, 2008Year in Clinical Cardiac Electrophysiology May 27, 2008:2075–81

Hauser et al. (53) reported a greater-than-expected rate ofailure in the Medtronic Sprint Fidelis model 6949 HV lead.ix of 583 Medtronic Sprint Fidelis model 6949 implantedetween September 2004 and February 2007 failed over theourse of 31 months (96% survival at 33 months). Only 1 of85 Medtronic Sprint Quattro model 6847 failed over theourse of 65 months (approximately 99% survival at 65onths). Analysis of the Food and Drug Administrationanufacturers User Facility Device Experience database and a

eview of the manufacturer’s analyses showed that the mostrequently reported defects for the Sprint Fidelis HV leadsere fracture of the pace-sense conductor or coil and the HV

onductor, leading to high impedances, noncapture, and inap-ropriate shocks (in response to nonphysiological noises).ecause both the Sprint Fidelis and the Sprint Quattro leadssed the same materials and construction, the cause for theigh failure rate was postulated to be the small diameter (6.3 F)f the Sprint Fidelis lead, which lowered the conductors’olerance to physical stress. In October 2007, Medtronicnnounced that the Sprint Fidelis lead had been withdrawnrom the market and the U.S. Food and Drug Administrationlaced these leads (268,000 leads implanted worldwide) in alass I recall. Medtronic analyses confirmed that the root causeas lead fracture and reported a 30-month survival rate of7.7% for the Fidelis leads, compared with 99.4% for the largerprint Quattro leads (54).Meanwhile, an entirely different potential complication

onfronts another HV lead. In a single-center, retrospectivenalysis of 2 families of HV leads (Riata 1580/1581 and590/1591, St. Jude Medical, Sylmar, California and Sprintidelis 6949, Medtronic), the investigators observed aignificantly greater incidence of subacute lead perforation1 to 10 days post-implant) with the Riata leads as com-ared with the Sprint Fidelis leads (55). Five perforationsccurred in 120 Riata leads, whereas none occurred in 111print Fidelis leads.However, the safety issue associated with the Riata leads

r any small-diameter leads has yet to be established. Themaller lead diameter cannot be the root cause of theerforation problem because the Medtronic Sprint Fidelis

eads have similar size. Lead perforation is a recognizedotential complication of implantation (0.1% to 0.8% foracemaker leads and 0.6% to 5.2% for ICD leads) (56). Itas been usually attributed to patients’ medical conditionsnd to implant techniques, especially when the data wererom a single center. However, since the publication of thiseport, several case reports describing acute and delayed�30 days) perforation with the small-diameter Riata HVeads have been published (57–59). On the other hand,nalyses performed by researchers at the St. Jude Medicalardiac Rhythm Management Division do not suggest a

reater incidence of perforation (60). Verbal and writtenncidence reports and returned product analysis showederforation rates of 0.057% for 86,000 Riata 8-F leads and.157% for 35,000 implanted 7-F leads. The overall perfo-

ation rate for the Riata leads was 0.33% to 0.34% in 2

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egistries administered by researchers from the St. Judeedical Cardiac Rhythm Management Division (ACT andPTIMUM). At this point, more data from multiple

ources will be needed before we can definitively identify ifhese leads are indeed unsafe.

eprint requests and correspondence: Dr. Melvin M. Schein-an, University of California San Francisco, 500 Parnassus Ave-

ue, Box 1354, San Francisco, California 94143. E-mail:cheinman@medicine.ucsf.edu.

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