C ardiac resynchronization therapy (CRT)has been shown by several large studies toimprove symptoms and mortality in a suit-
ably selected population of patients with systolic
m the Oxford Heart Centre, John Radcliffe Hospital, Oxford University
ding was received for this study. Dr. Gamble has received research fellow
nowledges support from the British Heart Foundation Centre of Research
llow at the University of Oxford. Dr. Betts has received research funding f
velopment and speaker fees from Boston Scientific Ltd. and Medtronic
tional Institute of Health Research Oxford Biomedical Research Centre. Drs
eived educational support from St. Jude Medical Ltd., Medtronic Ltd.,
nowledge support from Heart Research U.K.
nuscript received March 23, 2015; revised manuscript received July 20, 2
heart failure and prolonged QRS duration accordingto electrocardiogram data (1–3). CRT is mostcommonly achieved by transvenous placement of aleft ventricular (LV) lead into a tributary vein of the
Hospitals NHS Trust, Oxford, United Kingdom. No
ship funding from St. Jude Medical Ltd. Dr. Herring
Excellence (RE/08/004) and is a BHF Intermediate
rom St. Jude Medical Ltd. and honoraria for product
Ltd.; and he acknowledges support from the U.K.
. Gamble, Herring, Ginks, Rajappan, and Bashir have
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70
coronary sinus (CS); this procedure can betechnically demanding and may fail due toa variety of procedural or anatomic chal-lenges (4,5).
The present meta-analysis of the pub-lished data was performed to assess the suc-cess rates, causes of failure, and proceduralcharacteristics of CRT implantation bothduring the evolution of this procedure and inthe modern era.
METHODS
The meta-analysis was conducted according to thePreferred Reporting Items for Systematic Reviewsand Meta-Analyses statement (6). A systematic searchof PubMed, Web of Science, and the Cochrane Librarywas performed to identify relevant articles publisheduntil the end of 2014. The key words “cardiacresynchronization therapy,” “cardiac device,” and“CRT” were used. Hand-searching of the referencelists of included publications allowed identification ofarticles not found in the primary search strategy. Wealso searched relevant U.S. Federal Drug Adminis-tration device pre-market approval summary reports.
All publications reporting the results of attemptedimplantation of LV leads for CRT via the transvenousCS route were included, whether within a formal trialdesign or as part of a case series or similar report. Forthose studies comparing conventional CRT with adifferent procedure or control, the conventional CRTarm was included. Publications were excludedthat only reported outcomes after the implantationprocedure; that did not make it clear if any pro-cedures had failed; or that were entirely or largelyduplicates of previously reported data. The study wasdeliberately inclusive to include the maximum num-ber of patients to assess procedural success rates.
The titles of all publications identified werescreened, and those that did not meet the studycriteria were excluded. We subsequently reviewedthe abstracts of remaining publications and, ifnecessary, the publication text. Methodologicalquality was not assessed, but publications weredichotomized into randomized controlled trials(RCT) and others.
The number of patients in whom the implantationprocedure failed was recorded. Reasons for failure toplace a LV lead were recorded as absolute numbers inone of a series of pre-defined categories. In addition,reported population parameters from the trials wererecorded, as absolute numbers when provided ormean and SD. LV lead revision, when reported, wasassessed as a secondary data point. The absolute
numbers of revised LV leads and the study follow-uptimes were also recorded.
Given the large number of trials included over along time period, significant heterogeneity was ex-pected, and a random effects meta-analyticalapproach was therefore applied to all analyses. Thelogarithm ratio of the rate of failure was analyzed, andresults are presented back-transformed as the medianpercentage of implantation failures. For the investi-gation of temporal trends, studies were consideredaccording to the starting year of recruitment; if unre-ported, this was estimated from provided data. Thisapproach was used to dichotomize included studies,using the midpoint of the total time period of allstudies as the dividing point, and to assess temporalchanges and trends by using meta-regression. Sub-groups were compared by using mixed effects logisticmeta-regression, allowing for differential heteroge-neity between subgroups. Meta-analysis of eventcount data with relatively rare events, such as thesedata, is believed to be best performed with a binomialnormal model; this method provides appropriateweight to studies with low event numbers (7).
A random effects meta-analysis was also used toestimate the mean of population parameters, usingthe logarithm transform to estimate population pro-portions and treating continuous variables in thestandard meta-analytical manner; subgroups weresimilarly compared by using meta-regression. Weanalyzed lead revision as a mixed effects logisticregression meta-analysis of the incidence rate ofrevision. Several different LV lead classificationschemes have been used to describe the anatomiclocation of the final LV lead position, including a broadclassification as anterior, lateral, or posterior; accord-ing to the vein or vein territory used (8); or accordingto segment as anterior, lateral, posterolateral, orposterior. We recorded the absolute numbers ofleads in the positions described, as well as the pro-portion of leads in the lateral-posterolateral regiongenerally considered to be optimal (8), when this in-formation could be estimated from the provided data.Proportions were estimated by using methods similarto the aforementioned meta-analytical techniques.
Statistical analysis was performed using R version3.1 and the Metafor package, with use of the ggplot2package for graphs (9,10). A significance level of 0.05was used, and all testing was 2-tailed. All confidenceintervals (CIs) quoted are at the 95% level.
RESULTS
STUDIES INCLUDED. Figure 1 summarizes the selec-tion of the 164 included studies, which commenced
FIGURE 1 Flow of Publications Through the Review Process
FDA ¼ U.S. Federal Drug Administration.
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recruitment between 1997 and 2012 and were pub-lished between 2000 and 2014. Seven additionalstudies were found for which the only availablereport was in U.S. Federal Drug Administrationdocuments. A full list of included studies is detailedin the Online Appendix. Included studies involved29,503 patients in whom implantation of a LV lead forCRT was attempted.
CHARACTERISTICS OF INCLUDED PATIENTS. Summarycharacteristics of all included patients are detailed inTable 1. Characteristics are also further separated intoearly studies commencing recruitment before themidpoint of 2004 and later studies commencingrecruitment from January 2005 onward. The start andend dates of recruitment were estimated for 20% ofstudies.
Reporting of baseline patient details was inconsis-tent between studies, although some data were re-ported for 99% of patients. Several studies did notinclude within their reported number those patients inwhom implantation of a LV lead failed, and in otherstudies, data were reported for those who wereexcluded before implantation. Table 1 presents thepercentage of patients included in the studies in whicheach data point was reported, which was >80% for allparameters. There was significant heterogeneity in allparameters, with I2 values (a measure of study het-erogeneity) >95% for all parameters except the sexdistribution (80%). There was a significant decrease inmean QRS duration between the early and late timeperiods, although if the 9 studies specifically includingpatients with a narrow QRS were excluded, this dif-ference was reduced (after exclusion, early 163 ms[95% confidence interval [CI]: 159 to 167]; late 156 ms[95% CI: 152 to 160]; p ¼ 0.003).
TABLE 1 Summary Features of Patients in Included Studies
All Studies Earl
No. of studies 164
No. of patients 29,503 1
Median no. of patients per study (range) 102 (9–1,164) 123.5 (9
Mean study duration, yrs 2.5 (0–11) 2.8 (0
Median no. of centers (range) 1 (1–128) 6 (1
% Male 74.1 (72.4–75.8) 74.4 (7
Age, yrs 66.3 (65.3–67.3) 66.7 (6
% Ischemic etiology 50.3 (46.6–54.2) 51.7 (4
Device upgrade procedures, % 0.6 (0.4–1.1) 0.4 (0
LVEF, % 26 (24.5–27.7) 26 (2
NYHA functional class 2.8 (2.7–2.9) 2.8 (2
QRS duration, ms 155.1 (150.0–160.2) 160.1 (1
Unless otherwise indicated, values are median (95% confidence interval). *Mann-Whitn
LVEF ¼ left ventricular ejection fraction; NYHA ¼ New York Heart Association.
OCCURRENCE OF FAILURE TO PLACE AN LV LEAD. Theproportion of patients in whom it was not possible toplace a LV lead is shown in Table 2, and the data arepresented as a forest plot in Figure 2. The proportionof failed LV lead placements decreased steadily overthe time period by 0.48% per year (95% confidenceinterval [CI]: –0.28% to –0.69%; p < 0.001). Meta-regression of each half of the time period separatelyshowed a trend toward a significant decrease over theearly period (0.51% per year; 95% CI: –1.1% to 0.09%;p ¼ 0.095) but no significant change over the lateperiod (0.032% per year; 95% CI: –0.03% to 0.04%;p ¼ 0.86). Figure 3 presents a graphical representationof failure rates over time.
Comparisons were conducted according to meta-regression.
CI ¼ confidence interval; LV ¼ left ventricular.
FIGURE 2 Forest P
Forest plot of subgro
patients in whom lef
trial.
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As expected, and as is shown by the wide distri-bution of dots representing studies in Figure 3, therewas significant heterogeneity between studies in thisanalysis. I2 values were high at 79% across the wholetime period, although this value decreased from 89%in the early period to 69% in the later period. Therewas a strong trend toward a decrease in I2 across thetime period.
Thirty-three percent of included studies wereRCTs, which were larger than nonrandomizedstudies (median patients 175 vs. 89.5) and more likelyto be multicenter (median centers 19 vs. 1) andincluded 46% of patients. Failure rates in RCTs arealso shown in Figure 2. A more detailed comparison
lot of LV Lead Placement Failure Rates in Study Subgroups
up estimates and 95% confidence intervals (CIs) of the proportion of
t ventricular (LV) lead placement failed. RCT ¼ randomized controlled
between RCTs and other studies is given in OnlineTable 1.
Funnel plots of the rate of failure to place a leadsuggest significant underreporting of events in smallstudies (Online Figure 1). A modified Egger’s test alsosuggested significant underreporting (p < 0.001) (11).The trim-and-fill analysis, a method of estimatingthe likely result in the presence of additional hypo-thetical studies, suggests that 30 additional studieswith more events would have been expected to bereported, which would have increased the overallfailure rate estimate to 5% (95% CI: 4.3% to 5.9%).
REASONS FOR FAILURE TO PLACE AN LV LEAD. Thereasons for the inability to place an LV lead werereported in 44 (27%) studies and for 613 patients(39% of LV lead placement failures) (Figure 4).Inability to place an LV lead due to difficulties with CSaccess and navigation decreased significantly from53% (95% CI: 43% to 63%) to 30% (95% CI: 18% to46%; p ¼ 0.01) of failures, and failure due to a lack ofan anatomically suitable site (no suitable vessel, noacceptable threshold, lead instability, or phrenicnerve stimulation) increased significantly from39% (95% CI: 29% to 49%) to 64% (95% CI: 49% to77%; p < 0.001).
Nineteen (12%) trials, including 6,455 (22%) pa-tients, reported the failure rate at each attempt at LVlead implantation. The failure rate for the firstattempt was 7.2% (95% CI: 5.8% to 8.9%). The resultsof a second attempt were recorded for 187 (34%) ofthese attempts, which failed in 41% of patients.
LV LEAD POSITION. The final transverse plane loca-tion of the LV lead was reported for 29% of studiesand for 7,695 leads (26% of successful procedures).Forty-six percent of lead positions were reportedusing the vein territory (summarized in Figure 5), 23%used the anterior/posterior/lateral classification, 13%used the segment, and 19% reported the position onlyfor some leads.
Overall, 68% (95% CI: 56% to 79%) of leads werereported as being lateral or posterolateral. In the earlyperiod, 63% (95% CI: 48% to 76%) of leads wereplaced laterally or posterolaterally; in the late period,this increased to 81% (95% CI: 74% to 87%; p ¼ 0.01).The proportion of lateral or posterolateral leads wasnot a significant predictor of success rates accordingto meta-regression (p ¼ 0.1).
The combination of non-posterolateral leads andfailure to place an LV lead also decreased over time,with a more prominent decrease in the second half ofthe time period, from 38% (95% CI: 28% to 48%) to21% (95% CI: 15% to 28%; p ¼ 0.004). This outcome isshown graphically in Online Figure 2.
FIGURE 3 Temporal Trends in Failure to Place a LV Lead for CRT
The top panel shows percent failure rates according to the starting year of recruitment, the
study type, and number of patients. The line indicates the mean failure rate and the 95%
CIs (grey). The bottom panel shows the total number of subjects included in studies in
each year. Abbreviations as in Figure 2.
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LEAD AND DEVICE DESIGN. The only lead usedfrequently enough to make comparisons was the St.Jude Medical quadripolar lead (1458Q), which wasused in 14 nonrandomized studies. These studiesincluded 1,327 patients, and they commenced between2009 and 2011. The rate of failure to place an LV lead inin the quadripolar lead arms of these studies was 3.8%(95% CI: 2.9% to 4.9%), which was not significantlydifferent from other studies recruiting in the late timeperiod (p ¼ 0.19 by meta-regression).
LV LEAD REVISION. A total of 83 studies (including15,222 patients [52% of the total]) reported LV leadrevision rates over a mean follow-up of 8.0 months(range 1 to 24 months), including a total of 10,501patient-years of follow-up. These were used to derivethe rate of LV lead revision per 100 patient-years(Table 3). Figure 6 shows lead revision rates overtime. LV lead revision did not change significantlyover the whole time period (p ¼ 0.18) or over eitherhalf of the time period (p ¼ 0.16).
When lead revision was considered as a simpleproportion of patients, studies following up patientsfor 1 to 3, 3 to 6, and 6 to 12 months reported similarLV lead revision proportions (4.7%, 4.7%, and 4.4%,respectively), but studies with >12 months’ follow-upreported a higher proportion of lead revision (6.3%;p < 0.001 vs. others). However, when consideringlead revision rates as a function of study follow-uptime, studies with shorter follow-up time had sign-ificantly higher rates of displacement per 100 patient-years (p < 0.001). The available data were insufficientto assess differential revision rates of LV lead designs.There was significant heterogeneity in study out-comes across the whole time period, with an I2 of87%, which did not significantly change between theearly and late periods.
DISCUSSION
We provide data on success rates of LV lead im-plantation in a very large population of patients,including the majority of patients involved in thelandmark RCTs of CRT. The main finding of ouranalysis is that the rate of failure to place a LV leadvia the CS route has fallen consistently since theintroduction of the technique, with a reduction inthe rate of change in the last few years. The pre-dominant reasons for failure of an LV lead implan-tation have changed from those related to access andnavigation of the CS to there being no suitable targetvessel. The need for revision of the LV lead has notapparently changed significantly over the entire timeperiod. These figures provide a robust basis for
patient consent and benchmarking of CRT implan-tation programs.
FAILURE RATES FOR IMPLANTATION OF AN
LV LEAD. The improvement seen in success rateover time would be expected for many procedures.The techniques and equipment available for CRThave improved markedly over the time periodincluded, initially as equipment specifically designedfor CRT was developed, and more recently as it hasbeen refined (12–14). There is also undoubtedly anoperator learning curve that applies to this proce-dure, observed both within studies and within cen-ters (5,15–18). All of these effects would be expectedto have been more prominent over the earlier years ofthe technique.
The apparent slowing of the improvement in suc-cess rates seen over the second half of the studyperiod might be due to increasing numbers of cases in
FIGURE 4 Reasons for Failure to Place a LV Lead
Summary reasons for failure to place a left ventricular lead in the early and late periods.
The p values are from meta-regression.
FIGURE 5 Final Le
Final left ventricular
plane location is sho
Society of Cardiolog
tributaries of the cor
radiographic view ar
reported in 10 studie
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which the limiting factor becomes patient anatomy,rather than operator skill and equipment. Thispossibility is supported by the changes in reasonsfor implantation failure, in which failures caused bydifficulty accessing and navigating the CS werea major issue in the early period but less so inthe late period. This problem is less likely to beamenable to further technical developments that usea CS approach to implantation. Further lead designimprovements, such as an increased variety of lead
ft Ventricular Lead Positions
lead positions as estimated by using a meta-analysis. The transverse
wn on the left, as reported in the 21 studies using the European
y vein territory classification for 3,565 leads. The possible venous
onary sinus and their territories as seen in the left anterior oblique 40�
e shown. On the right, the cranio-caudal lead position is shown, as
s and 1,463 leads, and as seen in the right anterior oblique 30� view.
shapes, profiles, and multiple electrodes, might beexpected to result in a further limited reduction infailed implantation procedures, although we did notfind any such benefit from quadripolar leads in thisstudy. The MORE-CRT (More Options Available Witha Quadripolar LV Lead Provide In-clinic Solutions toCRT Challenges) study (19) did show a benefit ofquadripolar leads, driven apparently by easier im-plants but with a rate of failure to place a LV leadsimilar to the contemporary studies in our analysis. Apublication from our group has shown reducedphrenic nerve stimulation, LV lead revision, anddisplacement in patients with quadripolar leads, alsowith no apparent reduction in procedural success(20). A further factor in this lack of decline could beadditional operators starting to place LV leads at alower point in their individual learning curves.
It is notable how LV lead revision rates, after theinitial years of CRT, appear to have changed verylittle, unlike the rate of failure to place a LV lead. Theanalysis of lead revision rates is limited because thisaspect was a secondary outcome, but the results stillrepresent a large dataset.
The infrequent occurrence in contemporarystudies of failure to place a LV lead suggests thatsecond-line procedures for surgical or endocardiallead placement will need to be refined and central-ized into super-specialist centers for operators tohave adequate experience and skills in these tech-niques (21,22). This suggestion is supported by theextremely high 41% failure rate of repeat attempts atplacing LV leads in those patients in whom the firstprocedure had failed.
LV LEAD POSITION. Our data suggest that a signifi-cant proportion of patients receive an LV lead thatis positioned either anteriorly or apically, where itmay be less likely to benefit them, and that somesuccessful placements might be at the cost of a poorlead position (23,24). Reporting of lead positions andreasons for failed implantations were inconsistentacross studies, and these data were therefore gath-ered from a subselection of included papers. Leadposition in almost all studies was reported by theinvestigators (rather than centrally adjudicated),which is likely to reduce the accuracy of these databecause it has been previously shown that investi-gator reporting of lead position is variable (25). It ispossible that certain types of study are over-represented in this group, which could bias the data.In particular, studies reporting base to apex leadposition were frequently investigating quadripolarleads, which due to their design could be placed atthe apex but set up to pace from a more proximal pole
TABLE 3 LV Lead Revision Rates
All Studies Early Studies Late Studiesp Value
(Early vs. Late)
Studies reporting LVlead revision rates
83 48 35
No. of patients 15,222 8,732 6,490
Mean follow-up, months 8.2 8.3 8.2 NS (0.84)*
Lead revision rate, revisionsper 100 patient-yrs(95% CI)
*Mann-Whitney U test; other comparisons were conducted by using meta-regression.
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located basally. It is also impossible to definitivelystate that lead position was not optimal in those inwhom leads were placed in a non-classical position,as at least some included studies targeted leads basedon imaging data to positions optimized on a patient-specific basis (26,27).
CHARACTERISTICS OF PATIENTS UNDERGOING CRT
IMPLANTATION. There were only very small shifts inpatient characteristics over time, and these werelargely of such small magnitude as to be clinically andstatistically insignificant. A decrease in QRS durationwas seen in the included studies, even after thosestudies specifically including patients with a narrowQRS duration were excluded, but no clinically relevantchange in New York Heart Association functional classor left ventricular ejection fraction was reported.
Overall, it is notable how highly represented menin their sixth and seventh decade are in the CRT studypopulation, and how the research population isyounger than the heart failure population commonlyseen clinically. Some reported real-world CRT im-plantation data (28) are similar to those seen in thecurrent meta-analysis, but it is notable that recentU.S. data show that real-world patients are older andinclude more women (29). We did not attempt to
FIGURE 6 Left Ventricular Lead Revision Rates
Lead revision rates per 100 patient-years over time according to the start
mean failure rate and the 95% CIs. Abbreviations as in Figure 2.
make any links between study population parametersand success rates; these factors were not consistentlyreported for all patients in whom implantation wasattempted, and those in whom placements failedwere often excluded from study reporting. Hence,these population parameters can only provide asnapshot of CRT practice within trials.
STUDY LIMITATIONS. The conclusions of our analysisare limited by its meta-analytical nature and by thevariable completeness of data reporting in theincluded studies. The significantly lower failurerate in nonrandomized studies could reflect
ing year of study recruitment, the type, and size. The line indicates the
PERSPECTIVES
COMPETENCY IN MEDICAL KNOWLEDGE: The
rate of failure to place a left ventricular lead for CRT in
contemporary trials and series is 2.4%, and the rate of
lead revision is 5.7 per 100 patient-years. The rate of
failure to place a lead has decreased very significantly
from the rates reported in earlier trials of CRT. About
two-thirds of contemporary failures to place a left
ventricular lead are due to adverse distal venous
anatomy, and the remaining one-third are due to
challenging CS anatomy.
TRANSLATIONAL OUTLOOK: The incidence of
failure to place a LV lead is now so low that second-
and third-line surgical or interventional procedures
should be centralized into highly specialist centers.
Further developments in LV lead design should focus
on facilitating lead deployment into challenging distal
venous anatomy.
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underreporting of failed placements, due to eitheromission of reporting these or to publication bias. Thispossibility is supported by our statistical assessmentof a likely bias toward underreporting, although analternative explanation could be that these studieswere largely single-center series performed by expe-rienced operators. It is also possible that reporting ofthe reasons for failed implantation was inconsistent,with operators reluctant to report certain complica-tions such as CS dissection or perforation. These lim-itations may make the failure rate estimate from theRCT subgroup more reliable. It is notable in the graphof LV lead failure rates over time (Figure 3) that therewas a significantly lower failure rate in 2006, despite areasonable sample size in the year. No clear explana-tion for this anomaly was found, although it is possiblethat the aforementioned reasons might apply.
Almost no studies reported the characteristics ofpatients with failed LV lead placement. It was there-fore not possible to assess if any particular features ofthis population might have predisposed them toexperience a failed LV lead placement.
CONCLUSIONS
The rate of failure of LV lead implantation for CRT hasfallen very significantly since the introduction of thisprocedure, but the rate of change seems to haveslowed or stopped. The reasons for failure to place alead have changed from technical limitations to thosepredominantly due to adverse anatomy. Lead revi-sion rates have changed little since the introductionof CRT.
ACKNOWLEDGMENT The authors thank Dr.Jacqueline Birks of the Oxford Centre for Statistics inMedicine for invaluable assistance with the statisticalanalysis.
REPRINT REQUESTS AND CORRESPONDENCE: Dr.James H.P. Gamble, Oxford Heart Centre, John Rad-cliffe Hospital, Oxford University Hospitals NHSTrust, Oxford OX3 9DU, United Kingdom. E-mail:[email protected].
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