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CLINICAL RESEARCH

Opportunity to Increase Life Span inNarrow QRS Cardiac ResynchronizationTherapy Recipients by DeactivatingVentricular PacingEvidence From Randomized Controlled Trials

S.M. Afzal Sohaib, MBBS,* Judith A. Finegold, MA,* Sukhjinder S. Nijjer, MBCHB,* Ruhella Hossain, MBBS,*Cecilia Linde, MD,y Wayne C. Levy, MD,z Richard Sutton, MD,* Prapa Kanagaratnam, PHD,* Darrel P. Francis, MA,*Zachary I. Whinnett, PHD*

ABSTRACT

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OBJECTIVES This study examined the time course of clinical events in cardiac resynchronization therapy (CRT) trials.

BACKGROUND Recent randomized controlled trial results suggest that in heart failure with narrow QRS, biventricular

pacing (CRT) may increase mortality. The authors proposed implant complications as the cause, rather than a progressive

adverse physiological effect.

METHODS The study identified all trials comparing CRT with no CRT, which reported Kaplan-Meier curves in groups

defined by QRS: narrow, non–left bundle branch block (LBBB) broad, and LBBB broad. For each trial, the change in life

span every 3 months up to 3.5 years (the longest time for which data are available) was calculated and a power law was

fitted, that is, f timen.

RESULTS Four trials (MADIT-CRT [Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization

Therapy], RAFT [Resynchronization-Defibrillation for Ambulatory Heart Failure Trial], REVERSE [REsynchronization

reVErses Remodeling in Systolic left vEntricular dysfunction], and EchoCRT [Echocardiography Guided Cardiac Resynch-

ronization Therapy]), totaling 4,717 patients, reported curves for mortality or heart failure–related hospitalization, or for

mortality. In patients with LBBB broad QRS (within MADIT-CRT), life span gain increased in proportion to time1.94. In

contrast, in patients with non-LBBB broad QRS (within MADIT-CRT) and patients with narrow QRS (EchoCRT), life span was

lost in proportion to time1.92 and time,1.96 respectively. Hospitalization-free survival showed similar patterns.

CONCLUSIONS The nonlinear growth of life span gained when a CRT device is implanted in patients with LBBB broad

QRS is unfortunately mirrored by a similarly progressive loss in life span in narrow QRS heart failure. This suggests the

culprit is a progressive physiological effect of pacing rather than implant complications. If these data are not sufficient,

a randomized controlled trial of deactivating CRT in patients with narrow QRSmay now be needed, with a primary endpoint

of increasing survival. (J Am Coll Cardiol HF 2015;3:327–36) © 2015 by the American College of Cardiology Foundation.

m the *National Heart & Lung Institute, Imperial College, London, United Kingdom; yDepartment of Cardiology, Karolinska

iversity Hospital, Stockholm, Sweden; and the zDivision of Cardiology, University of Washington, Seattle, Washington. Drs.

haib, Finegold, Francis, and Whinnett are supported by the British Heart Foundation (FS/10/038, FS/13/44/30291, FS/11/92/

122, FS/14/25/30676). Dr. Nijjer is supported by the Medical Research Council (UK) (G1100443). Dr. Linde is supported by the

edish Heart Lung Foundation (Grants 20080498 and 20110406) and the Stockholm County Council (Grants

090376 and 20110610); was the principal investigator of REVERSE, a CRT study sponsored by Medtronic, Inc.; has received

ABBR EV I A T I ON S

AND ACRONYMS

AV = atrioventricular

CRT = cardiac

resynchronization therapy

ECG = electrocardiography

LBBB = left bundle branch

block

research gr

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of Health, A

Ware, Inc.,

received li

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Manuscript

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C ardiac resynchronization therapy(CRT) has strong evidence ofbenefit in patients with symptom-

atic heart failure with wide QRS and reducedleft ventricular ejection fraction (1–6). Morerecently it has been shown that the benefitsmay be limited to patients with left bundlebranch block (LBBB) (7,8) or very wide QRS(9). The benefits of CRT tend to be progres-

sive with life span gain occurring in a nonlinearmanner, suggesting an ongoing beneficial therapeuticeffect of biventricular pacing over a number of years(10). Over many years, however, patients with avariety of electrocardiographic (ECG) characteristicsreceived CRT implants. Data from the EuropeanCRT Survey suggest that as many as 32% of CRT recip-ients did not have underlying LBBB (11). Alternativeindications might have included mechanical dyssyn-chrony (11,12). In patients with narrow QRS, evenwhen selected for having mechanical dyssynchronyon echocardiography, CRT increased mortality by81% (p ¼ 0.02) in an international randomizedcontrolled trial (13). If this is true, a relatively largepopulation with CRT may be at potential risk ofadverse effects of CRT instead of benefit.

SEE PAGE 337

How these findings should affect clinical practicedepends on the cause of increased mortality, spe-cifically whether it is the result of implant compli-cations or an undesirable effect of ventricularpacing. Device implant complications will tend tocluster around the time of implant. For example, fordual-chamber pacing, one study shows that 75% ofall complications occurring over a 3-year periodoccur in the first 3 months post-implant (14), and forCRT, one center has reported that 59% of complica-tions in a mean follow-up of 2.7 years occur in thefirst 90 days post-implant (15). These event rates inthe first 3 months are 33 and 14 times, respectively,the rates in the remaining periods. If early implantcomplications are responsible, then there remainsno issue for the remainder of patients who did not

ants, speaker honoraria, and consulting fees from Medtronic, Inc

eMedical, Inc.; and is on theadvisoryboardofCardio3.Dr. Levyha

mgen, Thoratec, ResMed, Impulse Dynamics, Medtronic, Inc., an

GE Healthcare, Magellan Health, and PharmIn; and holds equit

censing for the Seattle Heart Failure Model from Impulse Dyna

rant from and is a consultant to Medtronic, Inc.; is on the

c.; and is a shareholder of Boston Scientific, Inc. and the Ame

tant to Medtronic, Inc. and Sorin. Dr. Whinnett acts as a consu

uthors have reported that they have no relationships relevant

received September 18, 2014; revised manuscript received Nove

have implant complications to continue with CRTpacing. In contrast, if the excess mortality is drivenby a detrimental effect from the action of pacingfrom CRT, then we may have an opportunity toimprove outcomes in surviving recipients by deac-tivating CRT.

These 2 possibilities should generate different timecourses of effect on mortality. Implant complicationspredominantly occur early, whereas progressiveconsequences of the detrimental activation sequenceof CRT compared with intrinsic conduction may occurgradually throughout follow-up. Mathematically, thepattern can be quantified by fitting the change in lifespan gain to a power law of time. In this study, we didthis with the data published by the randomizedcontrolled trials assessing CRT in heart failure.

METHODS

ELIGIBILITY AND SEARCH STRATEGY. We searchedMEDLINE and Google Scholar from inception toApril 2014 using the following search criteria: car-diac resynchronization therapy, survival, mortality,left bundle branch block, right bundle branchblock, and QRS morphology. Reference lists of theretrieved articles were hand-searched for additionalpublications.

We identified all randomized controlled trialscomparing CRT with no CRT (either CRT-pacemakeror CRT-defibrillator) and reported Kaplan-Meiersurvival curves for mortality stratified by QRSmorphology (LBBB, non-LBBB broad QRS, and narrowQRS). We similarly identified studies that providedKaplan-Meier curves for a combined endpoint such asdeath or heart failure hospitalization. Where studiesstratified results by ECGs, we checked whether theydescribed blinded analysis of ECG morphology.

CALCULATION OF LIFE SPAN GAIN OR LOST. Thesegmental area between the 2 curveswas calculated for3-month intervals. This represented life span gain orloss per patient randomized during that period. Thecumulative area between the curves up to each timepoint (life span gain up to that point per patient)

.; has received speaker honoraria and consulting fees

s received researchgrants fromtheNational Institutes

d HeartWare, Inc.; is a consultant to Novartis, Heart-

y in PharmIn. The University of Washington has

mics, Thoratec, and Epocrates. Dr. Sutton holds a

Speakers Bureaus of Medtronic, Inc. and St Jude

rican Society for Clinical Investigation. Dr. Francis

ltant to St. Jude Medical, Inc. and Medtronic, Inc.

to the contents of this paper to disclose.

mber 12, 2014, accepted November 14, 2014.

FIGURE 1 Calculation of Life Span Loss or Gain

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was also calculated. The process has been described(10,16) and is illustrated in Figure 1. As an example,to calculate the life years gained between 3 monthsand 6 months, the following calculation is used, witheach survival rate expressed as a proportion between0 and 1:

Life span gained ¼ survival in CRT

at 3 months � survival in controlsat 3 months

!þ

survival in CRT

at 6 months � survival in controlsat 6 months

!

2� 3 months

The cumulative gain in life span at any time

Graphical representation of how life span gain or lost due to an intervention is calculated at

any given time point. The black curve represents survival in a control group. The green

curve represents an intervention that prolongs life, and the area between the 2 represents

life span gained. The red curve represents an intervention for which life span is lost

because of an intervention, and the horizontal distance between the control and inter-

vention represents life span lost.

point was defined as the sum of the gains in each3-month period from zero to that time point. Thiscumulative life span gain at each 3-month intervalwas then re-expressed as a proportion of the total lifespan lost or gained at the end of the period analyzed.

Where studies randomized patients to CRT versuscontrol and separately reported results for LBBB andnon-LBBB broad QRS, we analyzed the Kaplan-Meiercurves for the 2 ECG morphologies separately. Eachtrial had different follow-up durations. The latest

TABLE 1 Characteristics of Included Studies

ECG Morphology Study Inclusion Criteria Total Participants Treatment n Control n

LBBB RAFT EF #30% 1,175 CRT-D 581 ICD 594

wide QRS QRS $120 (VVI 40/VVIR 50/

NYHA II–III DDI 40 [MVP]/

DDIR 50 [MVP])

MADIT-CRT EF #30% 1,281 CRT-D 761 ICD 520

QRS $130 (VVI/DDI 40)

NYHA I–II

REVERSE QRS $120 369 CRT-D/P on 256 CRT-D/P with CRT off 113

EF #40% (VVI 40)

NYHA I–II

Non-LBBB RAFT EF #30% 308 CRT-D 165 ICD 143

wide QRS QRS $120 (VVI 40/VVIR 50/

NYHA II–III DDI 40 [MVP]/

DDIR 50 [MVP])

MADIT-CRT EF #30% 537 CRT-D 328 ICD 209

QRS $130 (VVI/DDI 40)

NYHA I–II

REVERSE QRS $120 238 CRT-D/P on 160 CRT-D/P with CRT off 78

EF #40% (VVI 40)

NYHA I–II

Narrow QRS EchoCRT EF #35% 809 CRT-D 404 CRT-D with CRT off 405

QRS #130 (MVP)*

NYHA III–IV

Characteristics of the studies included in the analysis are described. For the control arms, where available, the modes of bradycardia pacing used (e.g. VVI) are given alongwith thelower rate limit (e.g., 40 beats/min). *Complete details of bradycardia pacing settings are not available; trial methods describe algorithms used to minimize ventricular pacing.

CRT ¼ cardiac resynchronization therapy; CRT-D ¼ cardiac resynchronization therapy with defibrillator; CRT-D/P ¼ cardiac resynchronization therapy with defibrillator/pacemaker; ECG ¼ electrocardiogram; EchoCRT ¼ Echocardiography Guided Cardiac Resynchronization Therapy; EF ¼ ejection fraction; ICD ¼ implantable cardioverter-defibrillator; LBBB ¼ left bundle branch block; MADIT-CRT ¼ Multicenter Automatic Defibrillator Trial with CRT; MVP ¼ minimized ventricular pacing; NYHA ¼ New York HeartAssociation; RAFT ¼ Resynchronization-Defibrillation for Ambulatory Heart Failure; REVERSE ¼ REsynchronization reVErses Remodeling in Systolic left vEntricular dysfunction.

FIGURE 2 Life Span Gained or Lost, Stratified by Electrocardiogram Morphology and Trial

(Top) Kaplan-Meier curves (cardiac resynchronization therapy [CRT] pacing arm in red and control arm in black). (Middle) The cumulative area between the trial arms, at

each time point, which represents the life span gain to that time point. Each study showed a different magnitude of impact in terms of absolute life span gain or loss.

(Bottom) These time courses are rescaled to reach 100% at the end of 3.5 years, so that the shape of development of life span gain or loss can be appreciated and

compared between the groups. EchoCRT ¼ Echocardiography Guided Cardiac Resynchronization Therapy; LBBB ¼ left bundle branch block; MADIT-CRT ¼ Multicenter

Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy.

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time point at which overall mortality data wereavailable consistently in all the trials was 3.5 years.The latest time point at which there were datadescribing death or heart failure hospitalizationavailable consistently in all the trials were 2 years.

DATA ANALYSIS. The effect on life span loss or gainper year was calculated for each ECG morphologygroup and fitted to a power law. All statistical ana-lyses were performed using the R software for sta-tistical computing version 3.0.2 (R Foundation forStatistical Computing, Vienna, Austria).

RESULTS

ELIGIBLE TRIALS. Data were available from 5 groupsin 4 trials totaling 4,717 patients. Three trials eachshowed data for patients with LBBB and non-LBBBbroad QRS (5,8,17), and 1 trial showed data for pa-tients with narrow QRS (13) (Table 1). In all cases, thedata were randomized comparisons between CRTand no CRT. All trials stratifying subjects byECG morphology had sufficient blinding of ECGmorphology to treatment and outcome: ECGs forMADIT-CRT (Multicenter Automatic Defibrillator

FIGURE 3 Survival Gained or Lost Stratified by Electrocardiogram Morphology

Proportion of life span gained or lost as a proportion of life span gained or lost at 3.5 years stratified by QRS morphology with curves fitted according to a power law.

(Left) narrow QRS. (Middle) non-LBBB. (Right). LBBB ¼ left bundle branch block.

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Implantation Trial-Cardiac Resynchronization Ther-apy) were analyzed in a core laboratory (7); ECGs forREVERSE (REsynchronization reVErses Remodelingin Systolic left vEntricular dysfunction) were analyzedby investigators blinded to treatment allocationand outcome, with a further 50 randomly chosenECGs assessed for intraobserver and interobservervariability (8); and QRS verification in RAFT(Resynchronization-Defibrillation for AmbulatoryHeart Failure Trial) was performed by 3 differentinvestigators blinded to treatment allocation andoutcomes (17).LIFE YEARS GAINED FROM CRT IN LBBB. In patientswith LBBB, the increase in life span achieved with CRTgrew with time, and much more than linearly. This isevident on assessment of the Kaplan-Meier data of theindividual trials (Figure 2). The best-fit power-law re-lationship was life span gain proportional to follow-uptime1.94 (R2¼0.998, p<0.0001) (Figure 3). This findingis consistent with a favorable physiological effect ofCRT, with progressively more life span gain incrementas the window of observation lengthens.LIFE YEAR IMPACT OF CRT IN NON-LBBB BROAD QRS.

In the non-LBBB broad QRS group, life span gain wasnumerically shorter in the patients randomized toCRT than control. This is evident in the curves of theindividual trials (Figure 2). The best-fit power-lawrelationship was life span gain proportional to follow-up time1.92 (R2 ¼ 0.996, p < 0.0001) (Figure 3). This isconsistent with there being an adverse effect of pac-ing from CRT, reducing life span further as the win-dow of observation lengthens.LIFE YEAR IMPACT FROM CRT IN NARROW QRS. Inpatients undergoing CRT with narrow QRS, life span

gain was numerically shorter in the patients ran-domized to CRT than control. This is visible in thecurves of the individual trials (Figure 2). The best-fitpower-law relationship was life span gain propor-tional to follow-up time1.96 (R2 ¼ 0.994, p < 0.0001)(Figure 3). This is consistent with there being anadverse effect of pacing from CRT, which producesprogressively more life span decrement as the win-dow of observation lengthens.IMPACT OF CRT ON SURVIVAL TIME FREE OF FIRST

HOSPITALIZATION. In the LBBB broad QRS group,time free from hospitalization and mortality wasnumerically longer in the patients randomized to CRTthan those randomized to control (Figure 4B). Thenarrow QRS group showed the opposite direction ofeffect (Figure 4A, left). The non-LBBB broad QRSgroup was mixed (Figure 4A, right).

DISCUSSION

Life span gain from CRT develops progressively withtime after implantation. The same shape of timecourse is seen in all 3 groups of patients, although thedirection of the effect is different. This is consistentwith the effect being mediated by the physiologicalconsequences of pacing.

The nonlinear growth of life span gain from CRTwas originally documented in trials that recruitedpatients with predominantly LBBB (10). The presentstudy separately analyzes patients with narrow QRSand patients with non-LBBB broad QRS. In thesepatients, CRT affects life span in a similarly shapedtime course, but, crucially, the effect is inverted,meaning there is a loss of life span that expands

FIGURE 4 Survival Time Free of Mortality or Hospitalization, Stratified by ECG Morphology and Trial

(A) (Top Left) Kaplan-Meier curves (CRT pacing arm in red and control arm in black). (Top Right) The cumulative area between the trial arms, at each time point, which

represents the gain in time free from hospitalization or mortality to that time point. Each study showed a different magnitude of impact in terms of absolute time gained

or lost free of mortality or hospitalization. (B) These time courses are rescaled to 100% at the end of 2 years, so that the shape of development of life span gain or loss

can be appreciated and compared between the groups. The panel with the smallest number of patients, the non-LBBB cohort of REVERSE, showed a nonsignificant trend

to benefit from pacing, but also manifested the greatest irregularity in the shape of the survival curves. This may be a manifestation of the greater susceptibility to

chance effects in small groups. RAFT ¼ Resynchronization-Defibrillation for Ambulatory Heart Failure; REVERSE ¼ REsynchronization reVErses Remodeling in Systolic

left vEntricular dysfunction; other abbreviations as in Figure 2.

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with approximately the square of time. This shapeimplies that this is due to the pacing effect of CRTrather than the initial risk associated with deviceimplantation.

MECHANISMS FOR ADVERSE IMPACT ON MORTALITY.

EchoCRT (Echocardiography Guided Cardiac Resyn-chronization Therapy) was the landmark studydemonstrating a clear increase in mortality in pa-tients undergoing CRT with narrow QRS, despite be-ing designed to identify and recruit those patientswith the best prospect of showing a benefit, namely,those with mechanical dyssynchrony.

The discussion of the EchoCRT publication sug-gested that implantation or subsequent lead manip-ulation might have caused the increased mortality

(13). However, this is not a plausible cause.First, the controls also underwent implantation. Sec-ond, mortality from implantation would be expectedto manifest early and not many years later as evi-denced in the data reported. Moreover, lead manipu-lation is a relatively unlikely cause of excessmortality, with infection being the most likely adverseoutcome (18). Our interpretation of the EchoCRTmortality data differs, because we observe that thereported mortality was driven by more than 20excess cardiovascular deaths (p < 0.01), of whichthe great majority were classified as “heart failure”or “arrhythmic events” rather than infection.Instead, the pattern suggests that CRT in these pa-tients unintentionally contributes to heart failureprogression.

FIGURE 4 Continued

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The main study publication does not appearto specify that the increase in mortality was a pro-gressive process more suggestive of a pathophysio-logical consequence of pacing rather than aprocedural consequence of the implant. By using asystematic approach, we identified the articles citingthis publication and examined them to see if theydrew this inference for themselves. We used GoogleScholar to identify citing documents. The 37 citingdocuments that were accessible from Imperial Col-lege, London, were read independently by 2 authors(S.M.A.S. and R.H.), with disagreements resolved by athird author (D.P.F.). A total of 25 documents (68%)mentioned that harm could be caused by CRT,whereas the remainder stated that there was nobenefit or did not comment. Of the 37 documents,only 2 (5%) demonstrated awareness that the harmwas due to the ongoing effects of pacing rather thanimplantation (Online Appendix).

DIFFERENCE BETWEEN DEVICE AND MEDICAL

THERAPY. If a drug is found to increase mortality,administration can be stopped. Moreover, informationon side effects in established drug therapy is readilyavailable for patients. Understanding benefits andadverse effects of implanted devices is more complex.For CRT in heart failure, for example, this informationis not fully established. If an adverse effect is sus-pected, interrupting therapy from a device that hasalready been implanted may appear unfamiliar anduncomfortable to both patients and physicians, unlessthe evidence to do so is very compelling. However,as information accumulates on who will benefit orbe harmed by CRT, it is becoming increasingly clearthat randomization to stopping CRT in an alreadyimplanted device may indeed be ethical, andperhaps may even be an ethical imperative. Thus, ifthe ongoing action of an implanted device is foundto be a progressive increase in mortality, there

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should be no reluctance in turning off the device inthe survivors.

CALL FOR A TRIAL: DEACTIVATING CRT IN PATIENTS

WITH NON-LBBB. It has been reported that onethird of recipients who already have CRT in Europehave neither underlying LBBB nor broad QRS (11).This amounts to approximately 20,000 individualsin Europe alone (19). In North America and else-where, there may be a similarly nontrivial number.This poses 2 opportunities. First, we may still beable to provide extra life span to a larger number ofpatients enrolled in these trials. Second, there is alarge pool of patients suitable for enrollment in arandomized controlled trial to answer definitivelythe hypothesis generated in this study. Such arandomized controlled trial would randomize thesepatients into leaving on versus turning off the CRTmode. This trial could be done at low cost becausethere is no need to implant a device, rather onlyreprogramming of the currently implanted device.The study would only require informed consent andonline randomization with follow-up limited to all-cause mortality in the interests of simplicity andto avoid the substantial costs of segregating causesof death or determining hospitalization. If thehazard ratio of 1.8 seen in EchoCRT is representa-tive, then the hazard ratio for switching off CRTwould be approximately 0.6, and therefore thenumber of patients and duration of follow-upneeded would be modest. Moreover, the potentialenrollees are already under regular routine devicefollow-up, and therefore the device communitycould conveniently approach all approximately40,000 patients promptly with minimal additionalvisits and cost.

A perceived difficulty may be explaining to thepatient why, having received a device, there is aproposal to deactivate the CRT element. One optionmight be to explain that the device can be pro-grammed in a variety of different ways, and it is notknown which is best. On the one hand, the atrioven-tricular (AV) delay could be set to always capture theventricle. On the other hand, it could be set to onlycapture the ventricle when natural ventricular acti-vation fails. Thus, the trial would have one arm usingthe currently programmed AV delay and the otherarm set to an AV delay longer than the intrinsic AVdelay, or set to a low backup rate solely to protectagainst bradycardia. In the case of narrow QRS, theinformed consent process would also require thatpatients are informed that new clinical trial evidence,which might not have been available at the time oftheir implant, suggests that such a device would

not usually be implanted with their current ECGmorphology, and that therefore switching off thepacing may be beneficial at present. However,should the QRS later broaden or the AV delay pro-long unacceptably, the device would already be inplace and the CRT function could then be usefullyswitched on. In the meantime, the patient would beprotected against asystole and (if it is a defibrillator)tachyarrhythmias.

Such a trial might enroll patients who werenot reliant on pacing, whose left ventricular leadwas functioning, whose native QRS was below athreshold duration and not in an LBBB pattern, andwho are free of serious noncardiac pathology thatwould limit life span. It might exclude patients withlong PR intervals because in this subgroup of non-LBBB there seems to be a beneficial effect of CRT(20). To minimize cost, the baseline data collectedcould be a simple set of widely available clinicalvariables, such as the elements of the modified Seat-tle Heart Failure score validated in SCD-HeFT (Sud-den Cardiac Death in Heart Failure Trial) (21,22).

It may be tempting to plan to restrict such a trial tothose who had not experienced a favorable symp-tomatic response. However, this may be unwise.Randomized trial data show that when comparedwith a placebo control arm, the incremental rate ofpatients who experience a symptomatic responsewith CRT pacing is only approximately 15% (23). Thismeans that the remainder of patients experiencing asymptomatic response with CRT, who are twice asnumerous in trials and may be more numerousoutside carefully monitored trial environments, havenot necessarily received any symptomatic benefitfrom the pacing itself because they would have felt aswell without it. Excluding symptomatic responderswould have the undesirable effect of causing patientswho express an optimistic view of their conditionand their care to miss the opportunity to participatein a trial that might have given them an opportu-nity for additional life span. Blinded randomizedcontrolled data on these patients would be themost valuable and practice-changing informationfrom such a trial because they may show that pa-tients who have CRT switched off gain a bettersymptomatic state than those who continue CRT. Ifthe consent process is designed carefully with asmuch opportunity for positive placebo, there mightbe net symptomatic improvements for both arms.Not every specialist might consider this trial neces-sary. Some may consider the information in Figures 2and 3 to be a sufficient indication of harm to meritroutine deactivation of biventricular pacing in thiscohort.

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There is some evidence to suggest that there is abenefit for CRT in those with a non-LBBB ECG, but avery broad QRS (>140 to 150 ms) (9). This trial wouldalso present an opportunity to address this question.STUDY LIMITATIONS. This study uses the publishedmortality time course data from randomized con-trolled trials of CRT versus no CRT, in studies thatpresent Kaplan-Meier curves for both arms of stratadefined by QRS characteristics. There are other trialsthat did not present data stratified by ECG mor-phology (3,24,25) and therefore were not included.Such information is likely to add further information,particularly in those with non-LBBB QRS widening.

Moreover, the evidence of increased mortality insubgroups of patients receiving CRT is only in theshort term. It is not known whether such effectsmight halt or reverse over longer periods of time.However, when the effects of CRT are beneficial, theytend to grow with time (10,26). It might not be pru-dent to hope that physiological harm would behavedifferently.

Except for the EchoCRT study, the studieseligible for our analysis covered the milder parts ofthe spectrum of heart failure. An even more pro-nounced effect on mortality in non-LBBB might beseen when the trials restricting inclusion to in-dividuals in New York Heart Association functionalclass III and IV are included.

Our study relied on the evaluation of the ECG asperformed in the original clinical trial. If that

classification was incorrect, then our analysis wouldsuffer accordingly.

CONCLUSIONS

The impact of CRT on survival time is nonlinearlydependent on the time window over which it iscalculated, growing approximately with the square oftime. In patients with underlying LBBB, this impact isa benefit, but in those without underlying LBBB, thisnonlinearly expanding impact on survival duration isadverse. The time course fits a progressive adversephysiological effect of pacing rather than implantcomplications. This suggests an opportunity forbenefit by deactivating pacing in such patients. Weshould consider a randomized controlled trial ofdeactivating CRT in recipients with narrow QRS orwithout underlying LBBB, with a primary endpoint ofsurvival.

ACKNOWLEDGMENTS The authors thank the Na-tional Institute for Health Research BiomedicalResearch Centre, based at Imperial College HealthcareNHS Trust and Imperial College London, for infra-structural support.

REPRINT REQUESTS AND CORRESPONDENCE: Dr.Darrel P. Francis, International Centre for CirculatoryHealth, Imperial College London, 59-61 North WharfRoad, London W2 1LA, United Kingdom. E-mail:darrel@drfrancis.org.

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KEY WORDS cardiac resynchronizationtherapy, heart failure, QRS morphology,survival

APPENDIX For a list of supplementalreferences, please see the online versionof this article.